Succinoylamino lactams as inhibitors of a-beta protein production

ABSTRACT

This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer&#39;s disease and Down&#39;s Syndrome.

RELATED CROSS-REFERENCES

This application is a continuation of U.S. patent application Ser. No. 11/175,644, filed Jul. 6, 2005, which is a divisional of U.S. patent application Ser. No. 10/285,776, filed Nov. 1, 2002, which is a divisional of U.S. patent application Ser. No. 09/506,360, filed Feb. 17, 2000, now U.S. Pat. No. 6,794,381, issued Sep. 21, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 09/370,089, filed Aug. 6, 1999, now abandoned, Provisional Application Ser. No. 60/095,698, filed Aug. 7, 1998 (expired), and Provisional U.S. Patent Application Ser. No. 60/120,227, filed Feb. 15, 1999 (expired), and Provisional Application Ser. No. 60/113,558, filed Dec. 23, 1998 (expired); the disclosures of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Aβ-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to β-amyloid production such as Alzheimer's disease and Down's Syndrome.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotional stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer's disease, Annu Rev Cell Biol, 1994, 10: 373-403).

Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down's Syndrome) and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).

Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plague is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Aβ, β-amyloid peptide, and sometimes β/A4; referred to herein as Aβ. In addition to deposition of Aβ in amyloid plaques, Aβ is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Aβ was first purified, and a partial amino acid reported, in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.

Compelling evidence accumulated during the last decade revealed that Aβ is an internal polypeptide derived from a type 1 integral membrane protein, termed β amyloid precursor protein (APP). β APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Aβ is derived from cleavage of β APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.

The existence of at least four proteolytic activities has been postulated. They include β secretase(s), generating the N-terminus of Aβ, a secretase(s) cleaving around the 16/17 peptide bond in Aβ, and γ secretases, generating C-terminal Aβ fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.

Several lines of evidence suggest that abnormal accumulation of Aβ plays a key role in the pathogenesis of AD. Firstly, Aβ is the major protein found in amyloid plaques. Secondly, Aβ is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of β APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other β APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human β APP. Fifthly, individuals with Down's syndrome have an increased gene dosage of β APP and develop early-onset AD. Taken together, these observations strongly suggest that Aβ depositions may be causally related to the AD.

It is hypothesized that inhibiting the production of Aβ will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Aβ production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Aβ in vivo.

Methods of treatment could target the formation of Aβ through the enzymes involved in the proteolytic processing of b amyloid precursor protein. Compounds that inhibit b or g secretase activity, either directly or indirectly, could control the production of Aβ. Advantageously, compounds that specifically target g secretases, could control the production of Aβ. Such inhibition of β or γ secretases could thereby reduce production of Aβ, which, thereby, could reduce or prevent the neurological disorders associated with Aβ protein.

PCT publication number WO 96/29313 discloses the general formula:

covering metalloprotease inhibiting compounds useful for the treatment of diseases associated with excess and/or unwanted matrix metalloprotease activity, particularly collagenase and or stromelysin activity.

Compounds of general formula:

are disclosed in PCT publication number WO 95/22966 relating to matrix metalloprotease inhibitors. The compounds of the invention are useful for the treatment of conditions associated with the destruction of cartilage, including corneal ulceration, osteoporosis, periodontitis and cancer.

European Patent Application number EP 0652009A1 relates to the general formula:

and discloses compounds that are protease inhibitors that inhibit Aβ production.

U.S. Pat. No. 5,703,129 discloses the general formula:

which covers 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives that inhibit Aβ production and are useful in the treatment of Alzheimer's disease.

None of the above references teaches or suggests the compounds of the present invention which are described in detail below.

SUMMARY OF THE INVENTION

One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Aβ protein or pharmaceutically acceptable salts or prodrugs thereof.

It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.

These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that compounds of Formula (I):

or pharmaceutically acceptable salt or prodrug forms thereof, wherein R³, R^(3a), R⁵, R^(5a), R⁶, A, Q, B, W, X, Y, and Z are defined below, are effective inhibitors of the production of Aβ.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Thus, in a first embodiment, the present invention provides a novel compound of Formula (I):

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   A is O or S; -   Q is —OR¹ or —NR¹R²; -   R¹, at each occurrence, is independently selected from:     -   H;     -   C₁-C₆ alkyl substituted with 0-3 R^(1a);     -   C₂-C₆ alkenyl substituted with 0-3 R^(1a);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);     -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and     -   5 to 10 membered heterocycle substituted with 0-3 R^(1b); -   R^(1a) at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(1b);     -   C₆-C₁₀ aryl substituted with 0-3 R^(1b); and     -   5 to 6 membered heterocycle substituted with 0-3 R^(1b); -   R^(1b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆     alkoxy, phenoxy, benzyloxy, C₃-C₁₀ carbocycle, C₆-C₁₀ aryl and 5 to     10 membered heterocycle; -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))C(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))S(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—S(═O)₂N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, 2, or 3; -   m is 0, 1, 2, or 3; -   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₆ alkyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is H, F,     Cl, Br, I, CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R⁵C;     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   R⁶ is H;     -   C₁-C₆ alkyl substituted with 0-3 R^(6a);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(6b); or     -   C₆-C₁₀ aryl substituted with 0-3 R^(6b); -   R^(6a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃; -   R^(6b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H and C₁-C₄ alkyl; -   W is (CR⁸R^(8a))_(p)—; -   p is 0, 1, 2, 3, or 4; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, 2, or 3; -   u is 0, 1, 2, or 3; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or     —OC(═O)—; -   Z is C₁-C₄ alkyl substituted with 0-3 R^(12b);     -   C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   B is a 5 to 10 membered lactam or thiolactam,     -   wherein the lactam or thiolactam is saturated, partially         saturated or unsaturated;     -   wherein each additional lactam carbon or thiolactam carbon is         substituted with 0-2 R¹¹; and,     -   optionally, the lactam or thiolactam contains a heteroatom         selected from —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-2 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or aryl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃,     acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄     haloalkyl, C₁-C₄ haloalkoxy, and C₁-C₄ halothioalkoxy; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,         C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, C₁-C₄     haloalkoxy, and C₁-C₄ halothioalkoxy; -   R¹⁴, at each occurrence, is independently selected from H, phenyl,     benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R^(14a) is H, phenyl, benzyl, or C₁-C₄ alkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, aryl-CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

[2] In a preferred embodiment the present provides

-   A is 0; -   Q is —NR¹R²; -   R¹, at each occurrence, is independently selected from:     -   H;     -   C₁-C₆ alkyl substituted with 0-3 R^(1a);     -   C₂-C₆ alkenyl substituted with 0-3 R^(1a); -   R^(1a), at each occurrence, is independently selected from H, OR¹⁴,     F, ═O, NR¹⁵R¹⁶, CF₃;     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);     -   phenyl substituted with 0-3 R^(1b); and     -   5 to 6 membered heterocycle substituted with 0-3 R^(1b);     -   R^(1b), at each occurrence, is independently selected from H,         OH, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₄         alkoxy, C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆     alkoxy, phenoxy, and benzyloxy; -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C (═O)— (CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—NHC(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)NH—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—NHS(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—S(═O)₂NH—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, 2, or 3; -   m is 0, 1, 2, or 3; -   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₆ alkyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is H, F,     Cl, Br, I, CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R⁵C;     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H;     -   C₁-C₆ alkyl substituted with 0-3 R^(6a);     -   C₃-C₆ carbocycle substituted with 0-3 R^(6b); or     -   C₆-C₁₀ aryl substituted with 0-3 R^(6b); -   R^(6a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃; -   R^(6b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H and C₁-C₄ alkyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, 2, 3, or 4; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, 2, or 3; -   u is 0, 1, 2, or 3; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or     —OC(═O)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a 6, 7, or 8 membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹, C(═O)R¹⁷,         C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

[3] In a further preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, or 2; -   m is 0, 1, or 2; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH, OR^(4a),     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is H, F,     Cl, Br, I CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R⁵C;     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H, methyl, or ethyl; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H, methyl, ethyl, propyl, and     butyl; -   W is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, or 2; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, or 2; -   u is 0, 1, or 2; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,         C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

[4] In a further preferred embodiment the present invention provides

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0 or 1; -   m is 0 or 1; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH,     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is H, F,     Cl, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b), phenyl substituted         with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, butoxy, or allyl; -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R⁵C;     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁶ is H; -   R⁷, at each occurrence, is independently selected from H, F, CF₃,     methyl, and ethyl; -   R^(7a), at each occurrence, is independently selected from H, F,     CF₃, methyl, and ethyl; -   R^(7b) is independently selected from H, methyl, and ethyl; -   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl; -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

[5] In a more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃,     -   —CH₂ (CH₃)₂, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃,     -   —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃,     -   —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂, —CH₂CH═C(CH₃)₂,         —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,         cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),         trans-CH₂CH₂CH═CH(CH₃);     -   —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),     -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,         cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,         cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, phenyl-CH₂—,     -   (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,         (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,         (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,         (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,         (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,         (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,         (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,         (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,         (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,         (3-Cl-4-F-phenyl)CH₂—,     -   phenyl-CH₂CH₂—,     -   (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,         (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—,         (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,         (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,         (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,         (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,         (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,         (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,         (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,         (3-F-5-Cl-phenyl)CH₂CH₂—, or -   R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂(CH₃)₂, —CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,     —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂,     —CH₂CH═CH₂, —CH═CHCH₃, cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),     trans-CH₂CH═CH(C₆H₅), —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃,     trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃),     trans-CH₂CH═CHCH₂(C₆H₅),     -   —C≡CH, —CH₂C₂≡CH, —CH₂C≡C(CH₃), —CH₂C≡C(C₆H₅) —CH₂CH₂C≡CH,         —CH₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅) —CH₂CH₂CH₂C≡CH,         —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂C≡C(C₆H₅)     -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,         cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—,         (3-CH₃-cyclobutyl)CH₂—,     -   cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—,         cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,         (3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,         (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, furanyl-CH₂—, thienyl-CH₂—,         pyridyl-CH₂—, 1-imidazolyl-CH₂—, oxazolyl-CH₂—, isoxazolyl-CH₂—,     -   phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,     -   (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,         pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,     -   isoxazolyl-CH₂CH₂—, -   W is a bond, —CH₂—, or —CH(CH₃)—; -   X is a bond; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or     —N(CH₃)—, -   Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,     3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,     2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,     2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,     3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,     3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl,     2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl,     4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,     thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,     1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,     cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl,     phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,     (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,     (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,     (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,     (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,     (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,     (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,     (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,     (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,     (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,     (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,     (furanyl)CH₂—, (thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,     (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,     (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,     (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,     (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-pipridinyl)CH₂—,     -   phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,         (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,         (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,         (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,         (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,         (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,         (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,         (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,         (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,         (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—,         (3-Cl-4-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—,         (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,         (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—,         (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—,         (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,         (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,         (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—,(thienyl)CH₂CH₂—,         (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,         (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,         (isoxazolyl)CH₂CH₂—,         (benzimidazolyl)CH₂CH₂—,(cyclopropyl)CH₂CH₂—,         (cyclobutyl)CH₂CH₂—,(cyclopentyl)CH₂CH₂—,         (cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, (N-pipridinyl) CH₂CH₂—, -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; -   R¹¹, at each occurrence, is independently selected from H, ═O,     methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; and -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical.

[6] In a futher more preferred embodiment the present invention provides

-   B is

[7] In an even more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is H, F,     CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R⁵C;     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹¹ is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O,     -   NR¹⁸R¹⁹, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

[8] In another even more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is H, F,     CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb) at each occurrence, is independently selected from H, OH, Cl,     F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl, ethyl,     propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, Cl, F, Br,     I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); and -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl.

[9] In another even more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹¹ is methoxy, ethoxy, propoxy, butoxy, Cl, F, ═O, NR¹⁸R¹⁹, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

[10] In another even more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is R⁴, -   R⁴ is C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R⁵C; or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   W is —CH₂—, or —CH(CH₃)—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, methyl, ethyl, propyl, butyl; -   R¹⁵, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, and butyl; and -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl).

[11] In another preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, or 2; -   m is 0, 1, or 2; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is H, F,     Cl, Br, I CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R⁵C;     -   C₆-C₁₀ aryl substituted with 0-3 R⁵C; or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H, methyl, or ethyl; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H, methyl, ethyl, propyl, and     butyl; -   w is —(CR⁸R^(8a))_(p)—; -   p is 0, 1, or 2; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, or 2; -   u is 0, 1, or 2; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     —C(═O)NR^(19b)—, —NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,         C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

[12] In a more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is R⁴, -   n is 0 or 1; -   m is 0 or 1; -   R⁴ is H, OH,     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb) at each occurrence, is independently selected from H, OH, Cl,     F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   B is a seven membered lactam,     -   wherein the lactam is saturated, partially saturated or         unsaturated;     -   wherein each additional lactam carbon is substituted with 0-2         R¹¹; and,     -   optionally, the lactam contains a heteroatom selected from —O—,         —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl; -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

[13] In an even more preferred embodiment the present invention provides

-   B is

[14] In a preferred embodiment the present provides

-   A is S; -   Q is —NR¹R²; -   R¹, at each occurrence, is independently selected from:     -   H;     -   C₁-C₆ alkyl substituted with 0-3 R^(1a);     -   C₂-C₆ alkenyl substituted with 0-3 R^(1a); -   R^(1a), at each occurrence, is independently selected from H,     -   OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃;     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(1b);     -   phenyl substituted with 0-3 R^(1b); and     -   5 to 6 membered heterocycle substituted with 0-3 R^(1b); -   R^(1b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R² is independently selected from H, NH₂, OH, C₁-C₆ alkyl, C₁-C₆     alkoxy, phenoxy, and benzyloxy; -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S (═O)— (CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—S(═O)₂—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n), —C(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—NHC(═O)—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—C(═O)NH—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—NHS(═O)₂—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—S(═O)₂NH—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, 2, or 3; -   m is 0, 1, 2, or 3; -   R^(3a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, or C₂-C₄ alkenyloxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₆ alkyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkenyl substituted with 0-3 R^(4a),     -   C₂-C₆ alkynyl substituted with 0-3 R^(4a),     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I, CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₁-C₆ alkoxy substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H;     -   C₁-C₆ alkyl substituted with 0-3 R^(6a);     -   C₃-C₆ carbocycle substituted with 0-3 R^(6b); or     -   C₆-C₁₀ aryl substituted with 0-3 R^(6b); -   R^(6a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, phenyl or CF₃; -   R^(6b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, aryl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H and C₁-C₄ alkyl; -   W is (CR⁸R^(8a))_(p)—; -   p is 0, 1, 2, 3, or 4; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkynyl and C₃-C₈     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, 2, or 3; -   u is 0, 1, 2, or 3; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₆ alkyl or C₃-C₈ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —N(R¹⁹)—,     C(═O)NR^(19b)—, NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—, —S(═O)₂NR^(19b)—,     —NR^(19b)S(═O)—, —S(═O)NR^(19b)—, —C(═O)O—, or —OC (═O)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a 6, 7, or 8 membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and — -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a); C₆-C₁₀ aryl         substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁸R¹⁹,     -   C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

[15] In a further preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0, 1, or 2; -   m is 0, 1, or 2; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH, OR^(14a),     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, Br, I CF₃,     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₆ alkyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkenyl substituted with 0-3 R^(5b);     -   C₂-C₆ alkynyl substituted with 0-3 R^(5b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5a) is H, OH, C₁-C₄ alkyl, C₁-C₄ alkoxy, C₂-C₄ alkenyl, or C₂-C₄     alkenyloxy; -   R^(5b), at each occurrence, is independently selected from:     -   H, C₁-C₆ alkyl, CF₃, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶;     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(5c);     -   C₆-C₁₀ aryl substituted with 0-3 R^(5c); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   R⁶ is H, methyl, or ethyl; -   R⁷, at each occurrence, is independently selected from H, OH, Cl, F,     Br, I, CN, NO₂, CF₃, and C₁-C₄ alkyl; -   R^(7a), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, CF₃, phenyl and C₁-C₄ alkyl; -   R^(7b) is independently selected from H, methyl, ethyl, propyl, and     butyl; -   W is (CR⁸R^(8a))_(p)—; -   p is 0, 1, or 2; -   R⁸ and R^(8a), at each occurrence, are independently selected from     H, F, C₁-C₃ alkyl, C₂-C₃ alkenyl, C₂-C₃ alkynyl and C₃-C₆     cycloalkyl; -   X is a bond;     -   C₆-C₁₀ aryl substituted with 0-3 R^(Xb);     -   C₃-C₁₀ carbocycle substituted with 0-2 R^(Xb); or     -   5 to 10 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   Y is a bond or —(CR⁹R^(9a))_(t)—V—(CR⁹R^(9a))_(u)—; -   t is 0, 1, or 2; -   u is 0, 1, or 2; -   R⁹ and R^(9a), at each occurrence, are independently selected from     H, F, C₁-C₄ alkyl or C₃-C₆ cycloalkyl; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—,     —N(R¹⁹)—C(═O)NR^(19b)—, NR^(19b)C(═O)—, —NR^(19b)S(═O)₂—,     —S(═O)₂NR^(19b)—, —NR^(19b)S(═O)—, or —S(═O)NR^(19b)—; -   Z is C₁-C₃ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₁₀ carbocycle substituted with 0-4 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b) at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₆ alkyl, C₁-C₄ alkoxy, C₁-C₄ haloalkyl, and C₁-C₄     haloalkoxy; -   B is a seven membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷, C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹,     S(═O)₂R¹⁷;     -   C₁-C₆ alkyl substituted with 0-1 R^(10a);     -   C₆-C₁₀ aryl substituted with 0-4 R^(10b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(10b); or     -   5 to 10 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₆ alkyl, C₁-C₄ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷,         C(═O)NR¹⁸R¹⁹, S(═O)₂NR¹⁸R¹⁹, CF₃;     -   C₁-C₆ alkyl substituted with 0-1 R^(11a);     -   C₆-C₁₀ aryl substituted with 0-3 R^(11b);     -   C₃-C₁₀ carbocycle substituted with 0-3 R^(11b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a C₃-C₆ carbocycle or a benzo fused     radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₆     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-3 R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, C₁-C₆ alkyl, C₁-C₄ alkoxy,     C₁-C₄ haloalkyl, and C₁-C₄ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₆ alkyl, or C₂-C₆′ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); -   R¹⁷ is H, aryl, (aryl)CH₂—, C₁-C₆ alkyl, or C₂-C₆ alkoxyalkyl; -   R¹⁸, at each occurrence, is independently selected from H, C₁-C₆     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and —S(═O)₂—(C₁-C₆     alkyl); and -   R¹⁹, at each occurrence, is independently selected from H, OH, C₁-C₆     alkyl, phenyl, benzyl, phenethyl, —C(═O)—(C₁-C₆ alkyl) and     —S(═O)₂—(C₁-C₆ alkyl); and -   R^(19b) is H, C₁-C₆ alkyl, C₃-C₈ cycloalkyl, phenyl, benzyl or     phenethyl.

[16] In a further preferred embodiment the present invention provides

-   R³ is —(CR⁷R^(7a))_(n)—R⁴,     -   —(CR⁷R^(7a))_(n)—S—(CR⁷R^(7a))_(m)—R⁴,     -   —(CR⁷R^(7a))_(n)—O—(CR⁷R^(7a))_(m)—R⁴, or     -   —(CR⁷R^(7a))_(n)—N(R^(7b))—(CR⁷R^(7a))_(m)—R⁴; -   n is 0 or 1; -   m is 0 or 1; -   R^(3a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, or butoxy; -   R⁴ is H, OH,     -   C₁-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-1 R^(4a),     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   C₆-C₁₀ aryl substituted with 0-3 R^(4b), or     -   5 to 10 membered heterocycle substituted with 0-3 R^(4b); -   R^(4a), at each occurrence, is independently selected from is     -   H, F, Cl, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁵ is H, OR¹⁴;     -   C₁-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5a) is H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy,     propoxy, butoxy, or allyl; -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃,     S(═O)₂CH₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂     haloalkoxy; -   R⁶ is H; -   R⁷, at each occurrence, is independently selected from H, F, CF₃,     methyl, and ethyl; -   R^(7a), at each occurrence, is independently selected from H, F,     CF₃, methyl, and ethyl; -   R^(7b) is independently selected from H, methyl, and ethyl; -   W is a bond, —CH₂—, —CH(CH₃)—, —CH₂CH₂— or —CH(CH₃)CH₂—; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb); -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, —N(CH₃)—,     or —N(CH₂CH₃)—, -   Z is C₁-C₂ alkyl substituted with 1-2 R¹²;     -   C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R¹² is C₆-C₁₀ aryl substituted with 0-4 R^(12b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(12b); or     -   5 to 10 membered heterocycle substituted with 0-3 R^(12b); -   R^(12b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, C₁-C₄ alkyl,     C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and C₁-C₂ haloalkoxy; -   B is a seven membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, C(═O)R¹⁷, C(═O)OR¹⁷;     -   C₁-C₄ alkyl substituted with 0-1 R^(10a);     -   phenyl substituted with 0-4 R^(10b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(10b); or     -   5 to 6 membered heterocycle optionally substituted with 0-3         R^(10b); -   R^(10a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, Cl, F, Br, I, ═O, CN, NO₂, NR¹⁵R¹⁶, CF₃, or phenyl     substituted with 0-4 R^(10b); -   R^(10b), at each occurrence, is independently selected from H, OH,     C₁-C₄ alkyl, C₁-C₃ alkoxy, Cl, F, Br, I, CN, NO₂, NR¹⁵R¹⁶, or CF₃; -   R¹¹, at each occurrence, is independently selected from     -   C₁-C₄ alkoxy, Cl, F, ═O, NR¹⁸R¹⁹, C(═O)R¹⁷, C(═O)OR¹⁷, CF₃;     -   C₁-C₄ alkyl substituted with 0-1 R^(11a);     -   phenyl substituted with 0-3 R^(11b);     -   C₃-C₆ carbocycle substituted with 0-3 R^(11b); or     -   5 to 6 membered heterocycle substituted with 0-3 R^(11b); -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical; -   R^(11a), at each occurrence, is independently selected from H, C₁-C₄     alkyl, OR¹⁴, F, ═O, NR¹⁵R¹⁶, CF₃, or phenyl substituted with 0-3     R^(11b); -   R^(11b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, C₁-C₄ alkyl, C₁-C₃ alkoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R¹⁴ is H, phenyl, benzyl, C₁-C₄ alkyl, or C₂-C₄ alkoxyalkyl; -   R¹⁵, at each occurrence, is independently selected from H, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁶, at each occurrence, is independently selected from H, OH, C₁-C₄     alkyl, benzyl, phenethyl, —C(═O)—(C₁-C₄ alkyl) and —S(═O)₂—(C₁-C₄     alkyl); -   R¹⁷ is H, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl,     4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl,     (4-methylphenyl)methyl, (4-trifluorophenyl)methyl, methyl, ethyl,     propyl, butyl, methoxymethyl, methyoxyethyl, ethoxymethyl, or     ethoxyethyl; -   R¹⁸, at each occurrence, is independently selected from H, methyl,     ethyl, propyl, butyl, phenyl, benzyl, and phenethyl; and -   R¹⁹, at each occurrence, is independently selected from H, methyl,     and ethyl.

[17] In a more preferred embodiment the present invention provides

-   or a pharmaceutically acceptable salt or prodrug thereof, wherein: -   R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂CH₂CH₂CH₃, —CH₂(CH₃)₂,     —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CF₃, —CH₂CF₃,     —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH═CH₂, —CH₂CH═CH₂, —CH₂C(CH₃)═CH₂,     —CH₂CH═C(CH₃)₂, —CH₂CH₂CH═CH₂, —CH₂CH₂C(CH₃)═CH₂, —CH₂CH₂CH═C(CH₃)₂,     cis-CH₂CH═CH(CH₃), cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),     trans-CH₂CH₂CH═CH(CH₃);     -   —C≡CH, —CH₂C≡CH, —CH₂C≡C(CH₃),     -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,         cyclohexyl-CH₂—, cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—,         cyclopentyl-CH₂CH₂—, cyclohexyl-CH₂CH₂—, phenyl-CH₂—,     -   (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,         (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,     -   (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—,         (2,5-diF-phenyl)CH₂—, (2,6-diF-phenyl)CH₂—,         (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,         (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—,         (2,5-diCl-phenyl)CH₂—, (2,6-diCl-phenyl)CH₂—,         (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,         (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—,         (3-Cl-4-F-phenyl)CH₂—,     -   phenyl-CH₂CH₂—,     -   (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—,         (2-Cl-phenyl)CH₂CH₂—, (3-Cl-phenyl)CH₂CH₂—,         (4-Cl-phenyl)CH₂CH₂—, (2,3-diF-phenyl)CH₂CH₂—,         (2,4-diF-phenyl)CH₂CH₂—, (2,5-diF-phenyl)CH₂CH₂—,         (2,6-diF-phenyl)CH₂CH₂—, (3,4-diF-phenyl)CH₂CH₂—,         (3,5-diF-phenyl)CH₂CH₂—, (2,3-diCl-phenyl)CH₂CH₂—,         (2,4-diCl-phenyl)CH₂CH₂—, (2,5-diCl-phenyl)CH₂CH₂—,         (2,6-diCl-phenyl)CH₂CH₂—, (3,4-diCl-phenyl)CH₂CH₂—,         (3,5-diCl-phenyl)CH₂CH₂—, (3-F-4-Cl-phenyl)CH₂CH₂—,         (3-F-5-Cl-phenyl)CH₂CH₂—, or -   R⁵ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH₂(CH₃)₂, —CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, —CH₂CH₂CH₂CH₂CH₃,     —CH(CH₃)CH₂CH₂CH₃, —CH₂CH(CH₃)CH₂CH₃, —CH₂CH₂CH(CH₃)₂, —CH(CH₂CH₃)₂,     —CF₃, —CH₂CF₃, —CH₂CH₂CF₃, —CH₂CH₂CH₂CF₃, —CH₂CH₂CH₂CH₂CF₃, —CH═CH₂,     —CH₂CH═CH₂, —CH═CHCH₃, cis-CH₂CH═CH(CH₃), trans-CH₂CH═CH(CH₃),     trans-CH₂CH═CH(C₆H₅), —CH₂CH═C(CH₃)₂, cis-CH₂CH═CHCH₂CH₃,     trans-CH₂CH═CHCH₂CH₃, cis-CH₂CH₂CH═CH(CH₃), trans-CH₂CH₂CH═CH(CH₃),     trans-CH₂CH═CHCH₂(C₆H₅),     -   —C≡CH, —CH₂C≡CH, —CH₂C═C(CH₃), —CH₂C≡C(C₆H₅) —CH₂CH₂C_(≡CH, —CH)         ₂CH₂C≡C(CH₃), —CH₂CH₂C≡C(C₆H₅) —CH₂CH₂CH₂C≡CH,         —CH₂CH₂CH₂C≡C(CH₃), —CH₂CH₂CH₂C≡C(C₆H₅)     -   cyclopropyl-CH₂—, cyclobutyl-CH₂—, cyclopentyl-CH₂—,         cyclohexyl-CH₂—, (2-CH₃-cyclopropyl)CH₂—,         (3-CH₃-cyclobutyl)CH₂—,     -   cyclopropyl-CH₂CH₂—, cyclobutyl-CH₂CH₂—, cyclopentyl-CH₂CH₂—,         cyclohexyl-CH₂CH₂—, (2-CH₃-cyclopropyl)CH₂CH₂—,         (3-CH₃-cyclobutyl)CH₂CH₂—, phenyl-CH₂—, (2-F-phenyl)CH₂—,         (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—, furanyl-CH₂—, thienyl-CH₂—,         pyridyl-CH₂—, 1-imidazolyl-CH₂—, oxazolyl-CH₂—, isoxazolyl-CH₂—,     -   phenyl-CH₂CH₂—, (2-F-phenyl)CH₂CH₂—, (3-F-phenyl)CH₂CH₂—,     -   (4-F-phenyl)CH₂CH₂—, furanyl-CH₂CH₂—, thienyl-CH₂CH₂—,         pyridyl-CH₂CH₂—, 1-imidazolyl-CH₂CH₂—, oxazolyl-CH₂CH₂—,     -   isoxazolyl-CH₂CH₂—, -   W is a bond, —CH₂—, or —CH(CH₃)—; -   X is a bond; -   Y is a bond, —CH₂—V—, —V—, or —V—CH₂—; -   V is a bond, —C(═O)—, —O—, —S—, —S(═O)—, —S(═O)₂—, —NH—, or     —N(CH₃)—, -   Z is phenyl 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl,     3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl,     2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl,     2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl,     3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl,     3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl,     2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl,     4-MeS-phenyl, 2-CF₃O-phenyl, 3-CF₃O-phenyl, 4-CF₃O-phenyl, furanyl,     thienyl, pyridyl, 2-Me-pyridyl, 3-Me-pyridyl, 4-Me-pyridyl,     1-imidazolyl, oxazolyl, isoxazolyl, 1-benzimidazolyl, cyclopropyl,     cyclobutyl, cyclopentyl, cyclohexyl, morpholino, N-piperinyl,     phenyl-CH₂—, (2-F-phenyl)CH₂—, (3-F-phenyl)CH₂—, (4-F-phenyl)CH₂—,     (2-Cl-phenyl)CH₂—, (3-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂—,     (2,3-diF-phenyl)CH₂—, (2,4-diF-phenyl)CH₂—, (2,5-diF-phenyl)CH₂—,     (2,6-diF-phenyl)CH₂—, (3,4-diF-phenyl)CH₂—, (3,5-diF-phenyl)CH₂—,     (2,3-diCl-phenyl)CH₂—, (2,4-diCl-phenyl)CH₂—, (2,5-diCl-phenyl)CH₂—,     (2,6-diCl-phenyl)CH₂—, (3,4-diCl-phenyl)CH₂—, (3,5-diCl-phenyl)CH₂—,     (3-F-4-Cl-phenyl)CH₂—, (3-F-5-Cl-phenyl)CH₂—, (3-Cl-4-F-phenyl)CH₂—,     (2-MeO-phenyl)CH₂—, (3-MeO-phenyl)CH₂—, (4-MeO-phenyl)CH₂—,     (2-Me-phenyl)CH₂—, (3-Me-phenyl)CH₂—, (4-Me-phenyl)CH₂—,     (2-MeS-phenyl)CH₂—, (3-MeS-phenyl)CH₂—, 4-MeS-phenyl)CH₂—,     (2-CF₃O-phenyl)CH₂—, (3-CF₃O-phenyl)CH₂—, (4-CF₃O-phenyl)CH₂—,     (furanyl)CH₂—,(thienyl)CH₂—, (pyridyl)CH₂—, (2-Me-pyridyl)CH₂—,     (3-Me-pyridyl)CH₂—, (4-Me-pyridyl)CH₂—, (1-imidazolyl)CH₂—,     (oxazolyl)CH₂—, (isoxazolyl)CH₂—, (1-benzimidazolyl)CH₂—,     (cyclopropyl)CH₂—, (cyclobutyl)CH₂—, (cyclopentyl)CH₂—,     (cyclohexyl)CH₂—, (morpholino)CH₂—, (N-pipridinyl)CH₂—,     -   phenyl-CH₂CH₂—, (phenyl)₂CHCH₂—, (2-F-phenyl)CH₂CH₂—,         (3-F-phenyl)CH₂CH₂—, (4-F-phenyl)CH₂CH₂—, (2-Cl-phenyl)CH₂CH₂—,         (3-Cl-phenyl)CH₂CH₂—, (4-Cl-phenyl)CH₂CH₂—,         (2,3-diF-phenyl)CH₂CH₂—, (2,4-diF-phenyl)CH₂CH₂—,         (2,5-diF-phenyl)CH₂CH₂—, (2,6-diF-phenyl)CH₂CH₂—,         (3,4-diF-phenyl)CH₂CH₂—, (3,5-diF-phenyl)CH₂CH₂—,         (2,3-diCl-phenyl)CH₂CH₂—, (2,4-diCl-phenyl)CH₂CH₂—,         (2,5-diCl-phenyl)CH₂CH₂—, (2,6-diCl-phenyl)CH₂CH₂—,         (3,4-diCl-phenyl)CH₂CH₂—, (3,5-diCl-phenyl)CH₂CH₂—,         (3-F-4-Cl-phenyl)CH₂CH₂—, (3-F-5-Cl-phenyl)CH₂CH₂—,         (3-Cl-4-F-phenyl)CH₂CH₂—, (2-MeO-phenyl)CH₂CH₂—,         (3-MeO-phenyl)CH₂CH₂—, (4-MeO-phenyl)CH₂CH₂—,         (2-Me-phenyl)CH₂CH₂—, (3-Me-phenyl)CH₂CH₂—,         (4-Me-phenyl)CH₂CH₂—, (2-MeS-phenyl)CH₂CH₂—,         (3-MeS-phenyl)CH₂CH₂—, (4-MeS-phenyl)CH₂CH₂—,         (2-CF₃O-phenyl)CH₂CH₂—, (3-CF₃O-phenyl)CH₂CH₂—,         (4-CF₃O-phenyl)CH₂CH₂—, (furanyl)CH₂CH₂—,(thienyl)CH₂CH₂—,         (pyridyl)CH₂CH₂—, (2-Me-pyridyl)CH₂CH₂—, (3-Me-pyridyl)CH₂CH₂—,         (4-Me-pyridyl)CH₂CH₂—, (imidazolyl)CH₂CH₂—, (oxazolyl)CH₂CH₂—,         (isoxazolyl)CH₂CH₂—,         (benzimidazolyl)CH₂CH₂—,(cyclopropyl)CH₂CH₂—,         (cyclobutyl)CH₂CH₂—,(cyclopentyl)CH₂CH₂—,         (cyclohexyl)CH₂CH₂—,(morpholino)CH₂CH₂—, (N-pipridinyl)CH₂CH₂—, -   B is a seven membered thiolactam,     -   wherein the thiolactam is saturated, partially saturated or         unsaturated;     -   wherein each additional thiolactam carbon is substituted with         0-2 R¹¹; and,     -   optionally, the thiolactam contains a heteroatom selected from         —O—, —S—, —S(═O)—, —S(═O)₂—, and —N(R¹⁰)—; -   R¹⁰ is H, methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; -   R¹¹, at each occurrence, is independently selected from H, ═O,     methyl, ethyl, phenyl, benzyl, phenethyl, 4-F-phenyl,     (4-F-phenyl)CH₂—, (4-F-phenyl)CH₂CH₂—, 4-Cl-phenyl,     (4-Cl-phenyl)CH₂—, (4-Cl-phenyl)CH₂CH₂—, 4-CH₃-phenyl,     (4-CH₃-phenyl)CH₂—, (4-CH₃-phenyl)CH₂CH₂—, 4-CF₃-phenyl,     (4-CF₃-phenyl)CH₂—, or (4-CF₃-phenyl)CH₂CH₂—; and -   alternatively, two R¹¹ substituents on the same or adjacent carbon     atoms may be combined to form a cyclopropyl, cyclobutyl,     cyclopentyl, cyclohexyl, or a benzo fused radical.

[18] In a futher more preferred embodiment the present invention provides

-   B is

[19] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2S,3R)N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide; -   (2S,3R)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide, -   (2R,3S)N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(phenethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-((4-fluorophenyl)methyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopropylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclobutylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopentylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclohexylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopropylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclobutylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclopentylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[(3S)-hexahydro-1-(cyclohexylethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[20] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[1,3-dihydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3-dihydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[1,3-dihydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[21] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-S-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-S-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-S-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-phenoxybenzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-trifluoromethylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(4-methylphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-S-(3-(2,4-dichlorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(3-(3-chloro-4-fluorophenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzophenon-3-yl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[6,7-dihydro-5-(3-(2-naphthyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide. -   (2R,3S)N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(phenethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-((4-fluorophenyl)methyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopropylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclobutylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopentylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclohexylmethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopropylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclobutylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[6,7-dihydro-5-(cyclopentylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[6,7-dihydro-5-(cyclohexylethyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[22] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide;     and -   (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.

[23] In another even more preferred embodiment the present invention provides compounds of Formula (I) selected from:

-   (2R,3S)N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide; -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide;     and -   (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide.

In another preferred embodiment of the present invention, Q is N(OH)H.

In another preferred embodiment of the present invention, Q is NH₂.

In another preferred embodiment

-   R³ is R⁴, -   R^(3a) is H, methyl, ethyl, propyl, or butyl; -   R⁴ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl -   R⁵ is C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl -   R^(5a) is H, methyl, ethyl, propyl, or butyl; and -   the total number of carbon atoms in R³, R^(3a), R⁵ and R^(5a) equals     seven or more.

In another preferred embodiment

-   R³ is R⁴; -   R^(3a) is H; -   R⁴ is C₁-C₄ alkyl substituted with 1-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₂-C₄ alkyl substituted with 0-3 R^(5b);     -   C₂-C₄ alkenyl substituted with 0-2 R^(5b); or     -   C₂-C₄ alkynyl substituted with 0-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   H, methyl, ethyl, propyl, butyl, CF₃, OR¹⁴, ═O;     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); and -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy.

In another preferred embodiment

-   R³ is R⁴; -   R^(3a) is H; -   R⁴ is C₂-C₄ alkyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkenyl substituted with 0-2 R^(4a),     -   C₂-C₄ alkynyl substituted with 0-2 R^(4a), -   R^(4a), at each occurrence, is independently selected from is     -   H, F, CF₃,     -   C₃-C₆ cycloalkyl substituted with 0-3 R^(4b),     -   phenyl substituted with 0-3 R^(4b), or     -   5 to 6 membered heterocycle substituted with 0-3 R^(4b); -   R^(4b), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy; -   R⁵ is C₁-C₄ alkyl substituted with 1-2 R^(5b); -   R^(5b), at each occurrence, is independently selected from:     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(5c);     -   phenyl substituted with 0-3 R^(5c); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(5c); and -   R^(5c), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy.

In another preferred embodiment

-   W is —(CH₂)_(p)—; -   p is 1, 2, or 3; -   X is a bond;     -   phenyl substituted with 0-2 R^(Xb);     -   C₃-C₆ cycloalkyl substituted with 0-2 R^(Xb); or     -   5 to 6 membered heterocycle substituted with 0-2 R^(Xb);     -   wherein the 5 to 6 membered heterocycle does not contain an oxo         or imino substitued ring atom; and -   R^(Xb), at each occurrence, is independently selected from H, OH,     Cl, F, NR¹⁵R¹⁶, CF₃, acetyl, SCH₃, S(═O)CH₃, S(═O)₂CH₃, methyl,     ethyl, propyl, butyl, methoxy, ethoxy, propoxy, C₁-C₂ haloalkyl, and     C₁-C₂ haloalkoxy.

In another preferred embodiment when R¹ is H, R² is hydroxy, and R¹¹ is H, then X is not a bond.

It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to descibe additional even more preferred embodiments of the present invention.

In a second embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.

In a third embodiment, the present invention provides a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I)

In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.

In a fourth embodiment, the present invention provides a method for the treatment of neurological disorders associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a metalloprotease inhibitor which inhibits γ-secretase activity.

In a preferred embodiment the neurological disorder associated with β-amyloid production is Alzheimer's Disease.

In a preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid.

In a more preferred embodiment, the metalloprotease inhibitor is a hydroxamic acid with an IC₅₀ value of less than 10 μM in the Aβ immunoprecipitation assay.

In a fifth embodiment, the present invention provides a method for inhibiting γ-secretase activity for the treatment of a physiological disorder associated with inhibiting γ-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits γ-secretase activity.

In a preferred embodiment the physiological disorder associated with inhibiting γ-secretase activity is Alzheimer's Disease.

In a sixth embodiment, the present invention provides a compound of Formula (I) for use in therapy.

In a preferred embodiment the present invention provides a compound of Formula (I) for use in therapy of Alzheimer's Disease.

In a seventh embodiment, the present invention provides for the use of a compound of Formula (I) for the manufacture of a medicament for the treatment of Alzheimer's Disease.

Definitions

As used herein, the term “Aβ” denotes the protein designated Aβ, β-amyloid peptide, and sometimes β/A4, in the art. Aβ is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829. The 43 amino acid sequence is:

1 Asp Ala Glu Phe Arg His Asp Ser Gly Tyr 11 Glu Val His His Gln Lys Leu Val Phe Phe 21 Ala Glu Asp Val Gly Ser Asn Lys Gly Ala 31 Ile Ile Gly Leu Met Val Gly Gly Val Val 41 Ile Ala Thr. However, a skilled artisan knows that fragments generated by enzymatic degradation can result in loss of amino acids 1-10 and/or amino acids 39-43. Thus, an amimo acid sequence 1-43 represents the maximum sequence of amino acids for Aβ peptide.

The term “APP”, as used herein, refers to the protein known in the art as b amyloid precursor protein. This protein is the precursor for Aβ and through the activity of “secretase” enzymes, as used herein, it is processed into Aβ. Differing secretase enzymes, known in the art, have been designated b secretase, generating the N-terminus of Aβ, a secretase cleaving around the 16/17 peptide bond in Aβ, and “γ secretases”, as used herein, generating C-terminal Aβ fragments ending at position 38, 39, 40, 41, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.

The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.

The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O), then 2 hydrogens on the atom are replaced.

When any variable (e.g., R^(5b)) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R^(5b), then said group may optionally be substituted with up to two R^(5b) groups and R^(5b) at each occurrence is selected independently from the definition of R^(5b). Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

As used herein, “alkyl” or “alkylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, “C₁-C₆ alkyl” denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred “alkyl” group, unless otherwise specified, is “C₁-C₄ alkyl”.

As used herein, “alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of “C₂-C₆ alkenyl” include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.

As used herein, “alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

“Alkoxy” or “alkyloxy” represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, “alkylthio” or “thioalkoxy” is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. “Counterion” is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.

“Haloalkyl” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. “Haloalkoxy” is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. “Halothioalkoxy” is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.

“Cycloalkyl” is intended to include saturated ring groups, having the specified number of carbon atoms. For example, “C₃-C₆ cycloalkyl” denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

As used herein, “carbocycle” is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred “carbocycle” are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

As used herein, the term “heterocycle” or “heterocyclic ring” is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms, preferably 1, 2, or 3 heteroatoms, independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.

Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.

As used herein, the term “aryl”, “C₆-C₁₀ aryl” or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Unless otherwise specified, “aryl” may be unsubstituted or substituted with 0 to 3 groups selected from H, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂, N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃, CH₂CH₃, CO₂H, and CO₂CH₃.

The phrase “additional lactam carbons and thiolactam carbons”, as used herein, is intended to denote the number of optional carbon atoms in the lactam ring or thiolactam ring B of Formula (I). Formula (I″):

represents the lactam ring B of Formula (I). The ring numbering shown for lactams of Formula (I″) applies to analogous thiolactams. Additional lactam carbons are carbons in lactam ring B other than the carbons numbered 2 and 3 in the backbone of the formula. The additional lactam carbons may be optionally replaced by a heteroatom selected from oxygen, nitrogen and sulfur. Lactam ring B contains 1, 2, 3, 4, 5, 6 or 7 optional carbons, wherein one optional carbon may optionally be replaced by a heteroatom, such that the total number of members of lactam ring B, including atoms numbered 1, 2 and 3 in the backbone, does not exceed 10. It is preferred that the total number of atoms of lactam ring B is 6, 7 or 8; it is more preferred that the total number of atoms of lactam ring B is seven. Examples of lactam ring B include:

and their thiolactam counterparts. The examples are not intended to limit the invention. Preferred examples of lactam ring B are B1, B2, B5, B6, B8, B9, B13, and B16; more preferred examples of lactam ring B are B1, B6, B8, B9, and B13. Preferred examples of substituent R¹⁰ or R¹¹ on lactam B are methyl, ethyl, phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-trifluorophenyl, (4-fluorophenyl)methyl, (4-chlorophenyl)methyl, and (4-trifluorophenyl)methyl.

The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior chemical activity over the opposite enantiomer. For example carbon 3 of lactam ring B Formula (I″) may exist in either an S or R configuration. Thus, an R or S configuration at carbon 3 in Formula (I″) is considered part of the invention. An example of such configuration includes,

but is not intended to be limited to this example of ring B. When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the carbon atoms to which R³ and R⁵ are attached may describe chiral carbons which may display superior chemical activity over the opposite enantiomer. For example, where R³ and R⁵ are not H, then the configuration of the two centers may be described as (2R,3R), (2R,3S), (2S,3R), or (2S,3S). All configurations are considered part of the invention; however, the (2R,3S) and the (2S,3R) are preferred and the (2R,3S) is more preferred.

The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

“Prodrugs” are intended to include any covalently bonded carriers which release the active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formula (I), and the like.

“Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

Synthesis

The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.

Methods for the synthesis of succinylamino lactams are known in the art and are disclosed in a number of references including PCT publication number WO 96/29313, which is hereby incorporated by reference.

Disubstituted succinate derivatives can be prepared by a number of known procedures. The procedure of Evans (D. A. Evans et al, Org. Synth. 86, p83 (1990)) is outlined in Scheme 1 where acylation of an oxazolidinone with an acylating agent such as an acid chloride provides structures 1. Alkylation to form 2 followed by cleavage of the chiral auxiliary and subsequent alkylation of the dianion of the carboxylic acid 3 provides a variety of disubstituted succinates which can be separated and incorporated into structures of Formula (I) by those skilled in the art. Additional examples are found in P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138, incorporated herein by reference.

Diastereomerically pure succinate derivatives can be accessed using the chemistry outlined below, adapted from P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138 incorporated herein by reference. This reference provides the synthesis below to obtain compound 9. Compound 11 is used as an intermediate and is prepared from 9 by hydrogenation of the allyl group followed by coupling of 9-fluorenemethanol under standard conditions using DCC and DMAP in CH₂Cl₂. Deprotection of the tert-butyl ester is accomplished by treatment with 50% trifluoroacetic acid.

Additional methods useful for the preparation of succinate derivatives are known by those skilled in the art. Such references include, McClure and Axt, Bioorganic & Medicinal Chemistry Letters, 8 (1998) 143-146; Jacobson and Reddy, Tetrahedron Letters, Vol 37, No. 46, 8263-8266 (1996); Pratt et al., SYNLETT, May 1998, p. 531; WO 97/18207; and WO 98/51665. The synthetic disclosures of WO97/18207 and WO 98/51665 are hereby incorporated by reference.

A variety of compounds of Formula (I) can be prepared by methods described in Scheme 4. The protected α-amine 3 of the α-amino-ε-caprolactam can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene's book “Protective Groups in Organic Synthesis”, like N-Boc using di-t-butyldicarbonate in an appropriate solvent like DMSO. A sulfur atom can be introduced into the ring providing L-α-amino-β-thio-ε-caprolactam according to the procedure in S. A. Ahmed et al, FEBS Letters, (1984), vol. 174, pages 76-9 (Scheme 3). One skilled in the art can extend this methodology to the synthesis of β-amino and oxygen containing rings by analogy. The sulfur-containing molecules can also be oxidized to the sulfoxide and sulfone by methods known to one skilled in the art.

The lactam nitrogen of compound 13 can be alkylated by generating the anion with bases such as LDA, lithium bis(trimethylsilyl)amide or sodium hydride in solvents like THF, with or without cosolvents such as DMPU or HMPA and reacting this with a variety of groups containing leaving groups (X″) like bromide, iodide, mesylate or tosylate. Alkylating agents such as α-bromo amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347, 695-698.

The N-Boc protecting group can be removed by any number of methods well known in the literature like TFA in methylene chloride to give the compound 15. The amine 15 can be coupled to an appropriately substituted carboxylic acid or acid chloride by methods well described in the literature for making amide bonds, like TBTU in DMF with a base like NMM to give the elaborated compound 16. Compounds 16 can be alkylated using standard bases like LDA, NaH, or NaHMDS to deprotonate the amide followed by addition of an alkylating agent with an appropriate leaving group like halide, mesylate, or triflate in an appropriate solvent to provide compounds 17 with an R⁶ substituent. The t-butyl ester is then removed by treatment with TFA in methylene chloride to give the carboxylic acid 17.

The final compounds 18 were prepared by treating the activated carboxylic acid of 17 with an appropriately substituted amine. For instance, activation of the carboxylic acid with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) or PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) or other coupling agents known to those skilled in the art allows condensation with ammonia to form primary amides. Similarly, condensation of the activated acid with hydroxylamine hydrochloride provides the hydroxamic acid, or reaction with a primary or secondary amine provides the substituted amine derivative. Activation of the acid with PyBrOP (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate) followed by addition of an alcohol and 4-dimethylaminopyridine allows formation of the ester directly. For additional acylation reactions see for example Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 475-479.

Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 5. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected hydroxylamine bound to polystyrene beads can be purchased from Novabiochem, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides trityl-linked hydroxylamine resin. Coupling of a fluorenylmethyl-protected succinic acid derivative such as 20 with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound hydroxamate 21. The Fluorenylmethyl ester can be removed using 20% piperidine in DMF to provide the free carboxylic acid which can be coupled to amines like the caprolactam 22 (which is available using chemistry outlined in Scheme 4) using PyBOP (benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate) and a suitable base like DIEA in DMF or NMP. The support-bound intermediate 23 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing dilute (5%) trifluoroacetic acid in CH₂CL₂ and purified by conventional chromatography.

General Procedure for Solid-Phase Synthesis According to Scheme 5.

Resin 20 of Scheme 5: Fmoc-protected resin 19 (2.0 g, 0.78 mmol/g, 1.56 mmol) is purchased from Novabiochem and swelled in 20 ml of CH₂Cl₂ for 1 hour. The CH₂Cl₂ is removed and the resin is then treated with 25% v/v piperidine in DMF (8 mL) and allowed to shake slowly for 16 h. The solvent was removed by filtration and the resin was shaken with an additional 8 mL of 25% v/v piperidine in DMF for 2 h at rt. The solvents were removed by filtration, and the resin 20 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂ and dried in vacuo.

Succinate 10 of Scheme 2: Succinate 9 is prepared according to the literature procedure (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138). Succinate 9 (17.8 g, 66 mmol) is dissolved in 250 mL of ethyl acetate and placed in a Parr shaker bottle. To the solution is added 890 mg of 5% palladium on carbon, and the bottle is pressurized to 40 psi with hydrogen gas and shaken for 2.5 h at rt. The hydrogen is removed and the palladium catalyst is removed by filtration through a pad of celite. Concentration of the ethyl acetate solution provides 17.5 g (98%) of succinate 10. No further purification is necessary. MS (M−H)⁺=271.

Succinate 21 of Scheme 5: Succinate 10 (6.3 g, 23.1 mmol) is dissolved in 125 mL of CH₂Cl₂ and 4.8 g (23.3 mmol) of dicyclohexylcarbodiimide is added. The solution is stirred at rt for 30 min and then 4.6 g (23.4 mmol) of 9-fluorenemethanol is added followed by 122 mg (1 mmol) of 4-dimethylaminopyridine. After 5 h of stirring at rt, the reaction solution was diluted with an additional 100 mL of CH₂Cl₂ and filtered through a pad of celite to remove precipitated dicyclohexylurea. The solution was then washed 3× with 50 mL of a 1N HCl solution, 3× with 50 mL of a saturated sodium bicarbonate solution, and 2× with 50 mL of brine. The crude product was dried over MgSO₄ and soncentrated onto 15 g of silica gel. Chromatography eluting with a gradient of 2.5% to 5% ethyl acetate/hexanes provided 6.4 g (61%) of the diester as an oil. The purified diester (6.4 g 14.2 mmol) is then dissolved in 25 mL of CH₂Cl₂, 25 mL of trifluoroacetic acid is added, and the reaction solution is stirred at rt for 2 h. The reaction solution is directly concentrated in vacuo to an oil which is then redissolved in 25 mL of toluene and reconcentrated, followed by drying in vacuo to provide 6.3 g (98%) of the desired succinate 9 as an oil which solidifies on standing. MS (M+Na)⁺=471, (M+2Na)⁺=439.

Caprolactam 23 of Scheme 5: Boc-caprolactam 14 (5.0 g, 21.9 mmol) is dissolved in 60 mL of THF and chilled to −78° C. To the chilled solution is added 24 mL of a 1.0 M solution of lithium bis(trimethylsilyl)amide in THF, and the solution was brounght to 0° C. and stirred for 15 min. To the anion solution was added 6.5 g (22 mmol) of 3-iodobenzyl bromide (Aldrich) and the the solution was allowed to warm to rt and stirred for 18 h. The reaction solution was diluted with 50 mL of water and extracted 3× with ethyl acetate. The combined organic layers were dried over MgSO₄ and concentrated in vacuo. The crude product was purified by chromatography eluting with a gradient of 5-20% ethyl acetate/hexanes to afford 7.0 g (72%) of the title compound as a white solid. MS (M+Na)⁺=467.

Resin 22 of Scheme 5: Resin 22 (2.0 g, 0.78 mmol/g, 1.56 mmol) was swollen in 3 mL of DMF. In a separate flask, 1.85 g (4.68 mmol) of succinate 21 was dissolved in 3 mL of DMF and 2.5 mL of N,N-diisopropylethylamine (14 mmol) wsa added, followed by 1.81 g (4.68 mmol) of HATU. The solution containing the active ester was added to the slurried resin and the reaction suspension was slowly shaken for 18 h. The resin was then washed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. Loading of the resin was determined by Fmoc quantitation to be 0.25 mmol/g, see Reddy, M. P.; Voelker, P. J. Int. J. Pept. Protein Res. 1998, 31, 345-348.

Resin 24 of Scheme 5: Resin 22 (2.0 g, 0.25 mmol/g, 0.5 mmol) was suspended in 10 mL of 25% piperidine in DMF. The suspended resin was shaken for 30 min at rt, and then the resin was washed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. Deprotected resin (1.0 g, 0.25 mmol) was swollen in 2 mL of DMF. To the slurry was added 650 mg (1.25 mmol) of PyBOP and 217 mL (1.25 mmol) of DIEA. Separately, 443 mg (0.97 mmol) of caprolactam 23 was dissolved in 2 mL of DMF and 436 mL (2.5 mmol) of DIEA was added. The caprolactam solution was added to the resin slurry and the resin was mixed for 18 h at rt. The solvents were then removed and the coupling was repeated, with shaking at rt for 6 h. The resin was then washed 3× with 10 mL of DMF, 3× with 10 mL of methanol, and 3× with 10 mL of CH₂Cl₂.

Products 25 of Scheme 5: A 70 mg (17.5 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.15 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60° C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3× with THF (2 mL), 3× with methanol (2 mL), 3× with water, and 3× with CH₂Cl₂. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH₂Cl₂ for 30 min. The solution ws filtered off and the resin was washed with an additional 2 mL of CH₂Cl₂ and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 13.0 to 6.0 mg (14-60%) of the final products.

Additional Examples of compounds of Formula (I) can be prepared as shown in Scheme 6. A suitable resin for solid phase synthesis such as Fmoc (Fluorenylmethylcarbonyl)-protected peptide amide linker (PAL)-derivatized polystyrene beads can be purchased from Perkin Elmer Biosystems, Inc. Deprotection of the Fmoc group under standard conditions using 20% piperidine in DMF provides the free benzylamine. Coupling of a succinic acid derivative such as 28 (which is available using chemistry outlined in Scheme 4) with a coupling agent such as HATU in a suitable solvent like DMF or N-methylpyrrolidinone provides the support-bound amide 29. The support-bound intermediate 29 can then be elaborated to biaryl structures of the type 24 using typical Suzuki coupling conditions employing a catalyst such as Palladium complexes like tetrakis(triphenylphosphine)-palladium with 2M aqueous sodium carbonate as a base in a suitable solvent like THF or DME and an excess of a boronic acid. The final compounds are liberated from the support employing 50% trifluoroacetic acid in CH₂Cl₂ and can be purified by conventional chromatography or preparative HPLC.

General Procedure for Solid-Phase Synthesis According to Scheme 6

Resin 27 of Scheme 6: Fmoc-protected PAL resin 26 (0.80 g, 0.50 mmol/g, 0.40 mmol) is purchased from Advanced Chemtech and swelled in 20 ml of CH₂Cl₂ for 1 hour. The CH₂Cl₂ is removed and the resin is then treated with 25% v/v piperidine in DMF (6 mL) and allowed to shake slowly for 1 h. The solvents were removed by filtration, and the resin 27 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. and dried in vacuo.

Acid 28 of Scheme 6: To a solution of 0.100 g (367 mmol) of succinate 10 dissolved in 2.0 mL of dry DMF was added 0.120 mL (1.10 mmol) of N-methylmorpholine. A second solution containing 0.139 g (0.403 mmol) of caprolactam 23 of Scheme 5 dissolved in 2.0 mL of DMF was then added. To the mixed solution was added 229 mg (0.440 mmol) of PyBop and the reaction solution was stirred for 16 h at rt. The reaction solution was diluted with water (20 mL) and extracted 3× with 100 mL of ethyl acetate. The combined organic layers were dried with Na₂SO₄ and concentrated under reduced pressure. The resulting oil was purified by chromatography eluting with a gradient of 5-20% ethyl acetate in hexanes to provide 0.195 g (0.360 mmol, 98%) of the tert-butyl ester of Acid 28 (MS M+Na=621). The purified ester (0.195 g, 0.360 mmol) was dissolved in 10 mL of 25% trifluoroacetic acid in CH₂Cl₂ and stirred for 2 h at rt. The solvents were removed under reduced pressure and the acid was redissolved in 5 mL of toluene and reconcentrated 2× to remove residual TFA. The crude acid was found to be pure by ¹H NMR and was used in Scheme 6 without further purification.

Resin 29 of Scheme 6. Resin 27 (800 mg, 0.40 mmol) was solvated in 4.0 mL of dry DMF and and 0.63 mL (3.6 mmol) of diisopropylethylamine was added followed by a solution of Acid 28 dissolved in 4 mL of DMF. To the slurry was then added 0.465 g (1.2 mmol) of HATU and the slurry was shaken for 26 h at rt. The solvents were removed by filtration, and the resin 29 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. and dried in vacuo.

Products 30 of Scheme 6: A 75 mg (0.38 mmol/g, 28.8 mmol) portion of resin 24 was suspended in 1 mL of THF in a screw-cap vial. To the slurry was added a boronic acid (0.33 mmol), 150 mL of a 2 M solution of sodium carbonate, and 15 mg (13 mmol) of tetrakis(triphenylphosphine)palladium. The vial was tightly closed and heated to 60° C. for 16 h using a dry heater on a shaker table. The solvents were then removed by filtration and the resin was washed 3× with THF (2 mL), 3× with methanol (2 mL), 3× with water, and 3× with CH₂Cl₂. The resins were then placed in a glass vial and cleaved with 1 mL of 5% trifluoroacetic acid in CH₂Cl₂ for 2 h. The solution was filtered off and the resin was washed with an additional 2 mL of CH₂Cl₂ and the combined filtrates were evaporated to dryness to yield the crude products 25. The products were purified by chromatography eluting with 10-100% ethyl acetate in hexanes to yield 0.5 to 2.0 mg (14-60%) of the final products.

The internal phenyl ring can be exchanged for a pyridine ring using chemistry outlined in Scheme 7. The chloromethyl pyidine 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6 Incorporated herein by reference. After freebasing the pyridine, alkylation with the Boc-caprolactam provides pyridine intermediate 34, which can be elaborated to the protected amide 35 with succinate 10. Substitution can then be introduced using Suzuki methodology employing a palladium source such as tetrakis(triphenylphosphine) palladium(0) or bis(diphenylphosphinoferrocene) palladium(II) dichloride and a suitable base such as sodium carbonate or triethylamine in a solvent such as THF or toluene containing 10% methanol. Stille chemistry is also possible using a suitable palladium source such as tetrakis(triphenylphosphine)palladium(0) and an aryl or vinyl tin derivative in a solvent such as benzene, toluene, or xylenes. The tert-butyl ester is then deprotected under standard acidic conditions using trifluoroacetic acid and the amide is formed under standard conditions to provide products 36.

General Procedure for Synthesis According to Scheme 7

The chloromethyl pyidine HCl salt 33 is prepared using a known procedure reported in Nutaitis, Charles F.; Ledeboer, Mark W. Org. Prep. Proced. Int. (1992), 24(2), 143-6.

Caprolactam 34: Pyridine HCl salt 33 (2.0 g, 8.3 mmol) is dissolved in 50 mL of a saturated NaHCO₃ solution and the solution is extracted with 30 mL of CH₂Cl₂ 3 x followed by concentration of the organic layers to provide the free base. Separately, 1.8 g (7.8 mmol) of caprolactam 13 is dissolved in 40 mL of dry THF and chilled to −78° C. To the solution was added 8.7 mL of a 1M solution of sodium bis(trimethylsilyl) amide. The solution was brought to 0° C. and stirred for 30 min. To the resultant anion was added a solution of 1.7 g (8.3 mmol) of pyridine 33 free base dissolved in 40 mL of THF. The resulting reaction solution was stirred at rt for 18 h and then heated to 50° C. and stirred an additional 3 h. The reaction solution was allowed to cool and then 50 mL of water was added and the aqueous layer was extracted 2× with 100 mL of ethyl acteate. The combined organic layers were dried and concentrated under reduced pressure to provide the crude product which was purified by chromatography eluting with 20 to 100% ethyl acetate in hexanes to provide 1.5 g (51%) of caprolactam 34 as an oil.

Amide 35: Caprolactam 34 (0.40 g, 1.0 mmol) is dissolved in 20 mL of 50% trifluoroacetic acid in CH₂Cl₂ and stirred at rt for 30 min. The solvents were then removed under reduced pressure and the resulting oil was redissolved in 5 mL of toluene and reconcentrated to remove residual TFA. Separately, 0.270 g (1.0 mmol) of succinate 10 was dissolved in 5.0 mL of dry DMF and 0.44 mL (4 mmol) of N-methylmorpholine was added followed by 0.50 g (1.3 mmol) of HATU and the resulting solution was stirred at rt for 30 min. The crude deprotected caprolactam from above was dissolved in 5.0 mL of dry DMF and added to the succinate solution and the resulting solution was heated to 50° C. and stirred for 2 days. The solution was then diluted with 20 mL of water and extracted with 3 50 mL portions of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to provide an oil which was purified by chromatography eluting with 20 to 50% ethyl acetate in hexanes to provide 0.40 g (70%) of the Amide 35.

Additional examples can be prepared by the method shown in Scheme 8. Coupling of an amine onto a commercially available aldehyde-derived resin 37 under conditions for reductive amination such as sodium tris(acetoxy)borohydride in CH₂Cl₂ containing 1% acetic provides a support-bound amine 38. The carboxylic acid 39 can then be coupled to the support-bound amine generating an amide 40 which can be liberated from the support employing trifluoroacetic acid in CH₂Cl₂.

General Procedure for Solid-Phase Synthesis According to Scheme 8

Resin 38 of Scheme 5: Aldehyde-derived resin 37 (200 mg, 0.5 mmol/g, 0.1 mmol) is purchased from Perkin Elmer Biosystems and swelled in 3 ml of CH₂Cl₂ for 1 hour. An amine (1.0 mmol), sodium tris(acetoxy)borohydride (106 mg, 0.5 mmol) and acetic acid (30 μL, 1%) are added and the reaction is shaken on a shaker table for 16 h at rt. The solvents were removed by filtration and the resin 38 was rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. and dried in vacuo.

Products 40 of Scheme 8: Carboxylic acid 39 (23 mg, 0.045 mmol), diisopropylethylamine (13 mL, 0.075 mmol) and HATU (17.1 mg, 0.045 mmol) were mixed in 0.5 mL of DMF for 30 min. Amine-derived resins 38 (30 mg, 0.015 mmol) were then added and the suspension was shaken at rt for 16 h. The solvents were removed by filtration and the resins were rinsed 3× with 20 mL of DMF, 3× with 20 mL of methanol, and 3× with 20 mL of CH₂Cl₂. The isolated resins were then cleaved by the addition of 0.50 mL of trifluoroacetic acid. The product solutions were concentrated and redissolved in 0.5 mL of methanol and reconcentrated 2× to remove residual TFA. Product yields ranged from 0-100% based on the structure of the amine.

The compounds of Formula (I) of the present invention can also be prepared from aminolactam or aminothiolactam 42 and succinic acid derivatives 41 using amide bond syntheses known in the art, including methods commonly used in peptide syntheses, such as HATU, TBTU, BOP, pyBOP, EDC, CDI, DCC, hydroxysuccinimide, mixed carboxylic anhydride, and phenyl ester mediated couplings, as illustrated in Scheme 9 for the synthesis of aminolactam or aminothiolactam 43, an embodiment of the present invention.

Depending on the structure of the final product, it is appreciated by those skilled in the art that protecting groups or precursor functionality convertable to the desired groups may be desireable. Protecting groups and their use in synthesis are described in Green and Wuts, Protective Groups in Organic Synthesis, (Wiley 1991). The use of protecting groups is further illustrated in Scheme 10, in which the succinate half-ester 44 (Becket et al., Synlett 1993, 137-138) is coupled to the aminobenzodiazepine 45 (Sherrill and Sugg, J. Org. Chem. 1995, 60, 730-734; Bock et al., J. Med. Chem., 1993, 36, 4276-4292) to give ester 46, followed by conversion of the ester group to the primary amide 47.

Methods for the synthesis of lactams as contemplated by the present invention in lactam ring B in Formula (I), including amino benzodiazepines, are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268, which is hereby incorporated by reference. Additional references include Bock, et al, J. Org. Chem., 1987, 52, 3232-3239 and Sherrill et al, J. Org. Chem., 1995, 60, 730-734; Walsh, D. A., Synthesis, September 1980, p. 677.

The synthesis of the thiolactams of the present invention (Formula (I), A=S) can be carried out using thiolactam intermediates (42, A=S), using the methods described above. The thiolactam intermediates may be prepared from suitably protected aminolactams employing methods known to those skilled in the art, using, for example, Lawessson's reagent, P4S10, or related methods (see Taylor et al., Bioorg. Med. Chem. Lett. 1997, 7 (4), 453-456; Schwarz et al., Tetrahedron, 1997, 53 (26), 8795-8806; Achour et al., Synth. Commun. 1994, 24 (20), 2899-2905; Buege et al., Arch. Pharm. 1994, 327 (2), 99-103; Levai, et al., Arch. Pharm. 1992 (325 (11), 721-726; Duhammel et al., Tetrahedron Asymmetry 1991, 2 (3), 203-206; Bodine et al., Synth. Commun. 1982, 12, 787). Deprotection of the amine, coupling to an appropriate succinate derivative and elaboration of the distal succinic acid derivative provides the desired thiolactams of the present invention.

EXAMPLES

Chemical abbreviations used in the Examples are defined as follows: “DMPU” for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, “TBTU” for O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and “BOP” for benzotriazol-1-yloxytris-(dimethylamino)phosphonium hexafluorophosphate. It is understood that one skilled in the art can discern compounds used in the synthesis of Examples of the invention may be referred to by structure and number. For example, Resin 20 refers to the resin of structure 20 in Scheme 5; succinate 9 refers to the structure 9 found in Scheme 2 which is a succinate compound.

“HPLC” is an abbreviation used herein for high pressure liquid chromatography. Reverse-phase HPLC was carried out using a Vydac C-18 column with gradient elution from 10% to 100% buffer B in buffer A (buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid).

Example 1 (2R,3S)N1-[(3S)-hexahydro-1-(3,3-diphenylpropyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (1a): Di-tert-butyldicarbonate (10.2 g, 46.7 mmoles) was added portion wise to a solution of L-(−)-α-amino-ε-caprolactam (5.0 g, 39.0 mmoles) in dimethyl sulfoxide (30 mL). After 5 h at rt, the reaction was partitioned between water (100 mL) and ethyl acetate. The combined organic extracts were washed successively with 1 M HCl (50 mL), brine, and dried (MgSO₄) and concentrated in vacuo. The residue was recrystallized in 1:1 v/v ether-hexanes, two crops yielded the desired product (6.26 g, 70%) as white solid. MS (M+H-BOC)⁺=129.

Step (1b): Triphenylphosphine (3.0 g, 11.4 mmoles) and carbon tetrabromide (3.75 g, 11.7 mmoles) were added successively to a cooled (0° C.) solution of 3,3-biphenyl-1-propanol (1.5 mL, 7.5 mmoles) in dichloromethane (20 mL). After 1.5 hours at rt, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexanes) to give the desired product (1.93 g, 93% yield) as a clear oil. MS (M-BrC₂H₄)⁺=167

Step (1c): A 1.0 M tetrahydrofuran solution of lithium bis(trimethylsilyl)amide (1.3 mL) was added over 15 minutes to compound of Step (1a) (0.29 g, 1.27 mmoles) in tetrahydrofuran (3 mL) and DMPU (2 mL) at −78° C. The iodo compound prepared from compound (1b) (0.85 g, 3.09 mmoles) by typical Finkelstein methodology, in tetrahydrofuran (4 mL) was added and the reaction was allowed to warm to rt slowly. This was stirred for 10 hours at ambient temperature, partitioned between water and ethyl acetate. The combined organic extracts were washed successively with water (20 mL), brine (20 mL), and dried (MgSO₄) and concentrated in vacuo. The resulting residue was purified by silica gel column (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes, 15:85) to give the desired product (0.16 g, 30%). MS (M-Ot-Bu)⁺=349.

Step (1d): Trifluoroacetic acid (3 mL) was added to a solution of compound of Step (1c) (0.16 mg, 0.38 mmoles) in dichloromethane (9 mL). After 2 h at rt, the solvent was removed in vacuo. The residual trifluoroacetic acid was removed by azeotrope with dichloromethane (50 mL), toluene (50 mL), and dichloromethane (50 mL) successively to give the desired product (0.17 g, 99%) as a yellow oil. MS (M+H)⁺=323.

Step (1e): 4-Methylmorpholine (0.6 mL, 5.46 mmoles) and TBTU (0.11 g, 0.34 mmoles) were added to a solution of succinate acid (P. Becket, M. J. Crimmin, M. H. Davis, Z. Spavold, Synlett, (1993), 137-138) (0.085 g, 0.31 mmoles) in N,N-dimethylformamide (3 mL). After 30 minutes at rt, the compound from step (1d) (0.17 g, 0.39 mmoles) was added to the mixture. The reaction was stirred for 16 h at rt, then partitioned between 1 M HCl (20 mL) and ethyl acetate. The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate (20 mL), water (20 mL), brine (20 mL), dried (MgSO₄) and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 7:93 gradient to ethyl acetate:hexanes 25:75) to give the desired product (120 mg, 67%) as a clear oil. MS (M+NH₄-Ot-Bu)⁺=521.

Step (1f): Trifluoroacetic acid (3 mL) was added to a solution of compound of Step (1e) (120 mg, 0.21 mmoles) in dichloromethane (9 mL). After 3 hours at rt, the mixture was concentrated in vacuo. The residual trifluoroacetic acid was removed by azeotrope with toluene (1×50 mL) and dichloromethane (1×50 mL). The residue was triturated with Et₂O:Hexanes 95:5, to give the desired product (75 mg, 70%) as a white solid. MS (M−H)⁻=519.

Step (1g): 4-Methylmorpholine (0.05 mL, 0.45 mmoles) and BOP (73 mg, 0.17 mmoles) were added to a solution of compound of Step (1f) (60 mg, 0.12 mmoles) in N,N-dimethylformamide (2 mL). Hydroxylamine (33 mg, 0.47 mmoles) was added to the mixture, the reaction was stirred for 16 h at rt, was concentrated in vacuo, was acidified with trifluoroacetic acid, then purified by reverse phase HPLC on a Vydac C-18 column, to give the desired hydroxamic acid as a white solid (45 mg, 75%). MS (M−H)⁻=534.

Example 2 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (2a): Triphenylphosphine (3.40 g, 13.0 mmoles) and carbontetrabromide (4.20 g, 13.0 mmoles) were added successively to a solution of m-phenoxybenzyl alcohol (1.5 mL, 8.6 mmoles). After 4 h at rt the mixture was concentrated and was purified by silica gel column (hexanes, then ethyl acetate:hexanes, 5:95) to give the desired bromide (1.3 g, 57%) as a yellow oil. MS (M-Br)⁺=183.

Step (2b): A 1 M solution of lithium bis(trimethylsilyl)amide was added dropwise to a solution of compound of Step (1a) (0.3 g, 1.31 mmoles) in tetrahydrofuran (5 mL) at −78° C. After 30 minutes a solution of compound of Step (2a) (0.43 g, 1.63 mmoles) in tetrahydrofuran (4 mL) was added to the mixture dropwise. The reaction was allowed to come to ambient temperature, stirred for 16 h, then partitioned between water and ethyl acetate. The combined organic extracts were washed successively with water (20 mL), brine (20 mL), dried (MgSO₄) and concentrated in vacuo. The crude residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 then ethyl acetate:hexanes, 15:85) to give the desired product (360 mg, 67%) as a clear oil. MS (M-Ot-Bu)⁺=337.

Step (2c): Trifluoroacetic acid (5 mL) was added to a solution of compound of Step (2b) in dichloromethane (15 mL). After 3 h at rt the solution was concentrated in vacuo. The residual trifluoroacetic acid was removed from residue by azeotrope with toluene (50 mL) then dichloromethane (30 mL) to yield the desired amine (390 mg, 99%) as a clear oil. MS (M+H)⁺=311.

Step (2d): Following a procedure analogous to the preparation of Step (1e), but using the compound from of Step (2c) (390 mg, 0.88 mmoles) the amide was prepared, The crude compound was purified by silica gel chromatography to give the desired product (0.38 g, 92%) as a yellow oil. MS (M-Ot-Bu)⁺=491.

Step (2e): Following a procedure analogous to the preparation of step (1f), but using the compound from Step (2d) (380 mg, 0.67 mmoles), the carboxylic acid was prepared. The product was precipitated from ethyl ether with hexanes, to give the desired acid (227 mg, 66%) as a white solid. MS (M−H)⁻=507.

Step (2f): Following a procedure analogous to the preparation of compound of Step (1 g), but using the compound from step (2e) (150 mg, 0.29 mmoles) the title compound was prepared. The crude was purified by reverse phase HPLC on a Vydac C-18 column to give the desired product (90 mg, 58%) as a white solid. MS (M−H)⁻=522.

Example 3 (2R,3S)N1-[(3S)-hexahydro-1-(phenyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Step (3a): Triethylamine (1.5 mL, 10.8 mmoles), copper (II) acetate (0.95 g, 5.2 mmoles) and phenylboric acid (1.6 g, 13.1 mmoles) were added successively to a solution of compound of Step (1a) (1.0 g, 4.4 mmoles) in dichloromethane (20 mL). After 2.5 h at rt, more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After an additional 3 hours at rt more phenylboric acid (0.5 g, 4.1 mmoles) was added to the mixture. After 65 h at rt, the mixture was filtered over celite. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 then 15:85) to give the desired product (250 mg, 19%). MS (M-Ot-Bu)⁺=231.

Step (3b): Following a procedure analogous to the preparation of compound of Step (2c), but using compound of Step (3a) (250 mg, 0.82 mmoles), the amine (300 mg, 99%) was prepared as a yellow oil. MS (M+H)⁺=205.

Step (3c): Following a procedure analogous to the preparation of compound of Step (1e), but using compound from Step (3b) (0.3 g, 0.94 mmoles), the amide was prepared. The residue was purified by silica gel chromatography (ethyl acetate:hexanes, 5:95 to 20:80 in 5% increments, 500 mL each ratio) to give the desired product (210 mg, 60%) as a clear oil. MS (M+H-t-Bu)⁺=403.

Step (3d): Following a procedure analogous to the preparation of compound of Step (1f), but using compound from sStep (3c) (200 mg, 0.44 mmoles) the acid was prepared. The crude oil was triturated with ether:hexanes 1:1 to give the desired acid (114 mg, 65%) as a white solid. MS (M-OH)⁺=385.

Step (3e): Following a procedure analogous to the preparation of compound of Step (1g), but using compound from Step (3d) (82 mg, 0.20 mmoles) the title compound was prepared. The crude product was purified by reverse phase HPLC on a Vydac C-18 column to give the desired product (80 mg, 94%). MS (M−H)-=416.

Example 4 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 3, compound of Step (2e) (100 mg, 0.20 mmol) was treated with HATU (O-(7-azabenzotriazol-1-yl)-1,1,3,3,-tetramethyluronium hexafluorophosphate) (114 mg, 0.30 mmol) and N-methyl morpholine (66 mL, 0.6 mmol) in 2 mL of DMF for 15 min at rt. A solution of 2.0 M methylamine in THF (0.2 mL, 0.4 mmol) was added and the reaction solution was stirred for 1 h at rt. The reaction solution was diluted with 1N HCl (5 mL) and extracted 3× with 10 mL of ethyl acetate. The combined organic layers were washed with a saturated sodium bicarbonate solution (5 mL) and brine (5 mL), dried over magnesium sulfate, and concentrated in vacou to provide the crude amide. Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=544.

Example 5 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-N4-(methyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with N,O-dimethylhydroxylamine hydrochloride (40 mg, 0.40 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=574.

Example 6 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(methoxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with O-methylhydroxylamine hydrochloride (40 mg, 0.40 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=560.

Example 7 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with a 2.0 M solution of ammonia in dioxane (0.2 mL, 0.4 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (30 mg, 30%). MS (M+Na)⁺=530.

Example 7A (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(amino)-2-(2-methylpropyl)-3-(propyl)-butanediamide

Following a procedure analogous to the preparation of Example 4, compound of Step (2e) (100 mg, 0.20 mmol) was activated and condensed with hydrazine (13 mg, 0.4 mmol). Purification by reverse phase HPLC on a Vydac-18 column provided the desired amide (11.1 mg, 21%). MS (M+Na)⁺=542.

Example 8 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

(8a) Compound 8a was synthesized following a procedure analogous to the preparation of the compound 1e, but using the caprolactam 2c (2.5 g, 5.89 mmol), succinate 9 (1.64 g, 6.0 mmol), and HATU instead of TBTU. The compound was purified by chromatogrphy eluting with 5% methanol in CH₂Cl₂ to afford 1.50 g (45%) of the desired ester.

(8b) The ester from 8a (1.18 g, 2.10 mmol) was dissolved in 10 mL of a 50% solution of trifluoroacetic acid in CH₂Cl₂ and stirred at rt for 2 h. The solvents were removed by concentration under reduced pressure and the crude product was dissolved in 10 mL of toluene and reconcentrated twice to remove residual TFA. The crude acid was used without further purification or characterization.

Following a procedure analogous to the preparation of Example 7, compound 8b (1.065 g, 2.10 mmol) was activated and condensed with an excess of gaseous ammonia. Purification by reverse phase HPLC on a Vydac-18 column provided 500 mg (47%) of the desired compound of Example 8. MS (M+Na)⁺=528.

Example 9 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(allyl)-butanediamide

Example 9 was synthesized following a procedure analogous to the preparation of Example 2, but using succinate 9 (Scheme 2). Purification by reverse phase HPLC on a Vydac-18 column provided 150 mg of Example 9. MS (M+Na)⁺=544.

Example 10 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 2,4-dichlorophenyl boronic acid. Purification afforded 6.0 mg (60%) of the desired product. MS (M+Na)⁺=598.

Example 11 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-fluorophenyl boronic acid. Purification afforded 5.0 mg (54%) of the desired product. MS (M+Na)⁺=548.

Example 12 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of the desired product. MS (M+Na)⁺=544.

Example 13 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-methoxyphenyl boronic acid. Purification afforded 3.0 mg (32%) of the desired product. MS (M+Na)⁺=560.

Example 14 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-methylphenyl boronic acid. Purification afforded 3.0 mg (33%) of the desired product. MS (M+Na)⁺=544.

Example 15 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-chloro-4-fluorophenyl boronic acid. Purification afforded 4.0 mg (41%) of the desired product. MS (M+Na)⁺=582.

Example 16 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 4-trifluoromethylphenyl boronic acid. Purification afforded 4.0 mg (40%) of the desired product. MS (M+Na)⁺=598.

Example 17 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-methoxyphenyl boronic acid. Purification afforded 4.1 mg (44%) of the desired product. MS (M+Na)⁺=560.

Example 18 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 3-fluorophenyl boronic acid. Purification afforded 3.5 mg (38%) of the desired product. MS (M+Na)⁺=548.

Example 19 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 2-methoxyphenyl boronic acid. Purification afforded 1.3 mg (14%) of the desired product. MS (M+Na)⁺=560.

Example 20 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-1H-azepin-3-yl]-N4-(hydroxy)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 5 was followed using 2-naphthyl boronic acid. Purification afforded 3.0 mg (31%) of the desired product. MS (M+Na)⁺=580.

It will be understood by one skilled in the art that Scheme 6 can be followed in a manner analogous to the procedure for Scheme 5.

Example 21 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-methoxyphenyl boronic acid. Purification afforded 0.5 mg of the desired product. MS (M+Na)⁺=544.

Example 22 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 3-fluorophenyl boronic acid. Purification afforded 1.6 mg of the desired product. MS (M+Na)⁺=532.

Example 23 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-trifluoromethylphenyl boronic acid. Purification afforded 0.7 mg (4.3%) of the desired product. MS (M+Na)⁺=582.

Example 24 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 2,6-dichlorophenyl boronic acid. Purification afforded 1.8 mg (11%) of the desired product. MS (M+Na)⁺=582.

Example 25 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-tolyl boronic acid. Purification afforded 1.8 mg (12%) of the desired product. MS (M+Na)⁺=528.

Example 26 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-methoxyphenyl boronic acid. Purification afforded 0.5 mg (3.3%) of the desired product. MS (M+Na)⁺=544.

Example 27 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 4-fluoro-3-chlorophenyl boronic acid. Purification afforded 0.5 mg (3.3%) of the desired product. MS (M+Na)⁺=567.

Example 28 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 2-methoxyphenyl boronic acid. Purification afforded 0.8 mg (5.3%) of the desired product. MS (M+Na)⁺=544.

Example 29 (2R,3S)N1-[(3S)-hexahydro-1-(3-(2-methoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 6 was followed using 2-methoxyphenyl boronic acid. Purification afforded 1.5 mg (10%) of the desired product. MS (M+Na)⁺=544.

It will be understood by one skilled in the art that Scheme 7 can be followed in a manner analogous to the procedure for Schemes 5 and 6.

Example 30 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-methoxyphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Amide 35 of Scheme 7 (0.10 g, 0.18 mmol) was dissolved in 5 mL of toluene and 41 mg (0.27 mmol) of 4-methoxyphenyl boronic acid was added, followed by 31 mg (0.0147 mmol) of tetrakis(triphenylphosphine)palladium, 0.5 mL of a 2M sodium cabonate solution and 0.5 mL of methanol. The reaction solution was heated to reflux for 16 h and then allowed to cool to rt. The reaction solution was diluted with 10 mL of water and extracted 2× with 50 mL of ethyl acetate. The combined organic layers were dried and concentrated and the resulting oil was purified by chromatography eluting with 30 to 100% ethyl acetate in hexanes as a solvent to provide 30 mg (29%) of biaryl product. MS (M+H)⁺=580.

The purified biaryl product was dissolved in 10 mL of 1:1 trifluoroacetic acid/CH₂Cl₂ and stirred at rt for 2 h. The solvents were then removed under reduced pressure and the resulting oil was redissolved in 5 mL of toluene and reconcentrated to remove residual TFA. The crude acid (25 mg, 0.047 mmol) was then dissolved in 1 mL of DMF and 10 mL of N-methylmorpholine (0.094 mmol) and 42 mg (0.062 mmol) HATU were added and the reaction solution was stirred at rt for 45 min. Gaseous ammonia was then bubbled in at a gentle rate for about 1 minute and the solution was stirred for an additional 1 min. The reaction solution was then diluted with 10 mL of water and extracted 3× with 30 mL of ethyl acetate. The combined organic layers were dried and concentrated under reduced pressure to a solid which was purified by reversed phase HPLC to provide 3.5 mg (10%) of the compound of Example 30 as its trifluoroacetic acid salt. MS (M+H)⁺=523.

Example 31 (2R,3S)N1-[(3S)-hexahydro-1-(3-(4-trifluoromethylphenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for the compound of Example 30 was followed using 4-trifluoromethylphenyl boronic acid. Purification by HPLC afforded 6.0 mg of the desired product from as its trifluoroacetic acid salt. MS (M+Na)⁺=583.

Example 32 (2R,3S)N1-[(3S)-hexahydro-1-(3-(3-chloro-4-fluorophenyl)pyrid-5-ylmethyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

Amide 35 (0.30 g, 0.54 mmol) was dissolved in 3 mL of DMF and 123 mg (0.70 mmol) of 4-methoxyphenyl boronic acid was added, followed by 44 mg (0.0543 mmol) of bis(diphenylphosphinoferrocene) palladim (II) dichloride and 1.0 mL (7.18 mmol) of triethylamine. The reaction solution was heated to 80° C. for 24 h and then allowed to cool to rt. The reaction solution was diluted with 10 mL of water and extracted 2× with 50 mL of ethyl acetate. The combined organic layers were dried and concentrated and the resulting oil was purified by chromatography eluting with 20 to 100% ethyl acetate in hexanes as a solvent to provide 140 mg (50%) of biaryl product. MS (M+Na)⁺=624.

The general procedure reported for the compound of Example 30 was then followed to provide the amide. Purification by chromatography eluting with 20 to 100% ethyl acetate in hexanes afforded 45 mg of the desired product of Example 32 as its trifluoroacetic acid salt. MS (M+Na)⁺=567.

Example 33 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(butyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using butylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 100% of the desired product. MS (M+Na)⁺=586.

Example 34 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(2-furylmethyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using 2-furylmethylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 75% of the desired product. MS (M+Na)⁺=610.

Example 35 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cyclopentyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using cyclopentylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 42% of the desired product. MS (M+Na)⁺=598.

Example 36 (2R,3S)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-N4-(cinnamyl)-2-(2-methylpropyl)-3-(propyl)-butanediamide

The general procedure reported for Scheme 8 was followed using cinnamylamine. Analysis by ¹HNMR integration relative to an internal standard revealed a yield of 100% of the desired product. MS (M+Na)⁺=646.

Example 37 (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide

3-Bromomethylbenzophenone. A solution of 3-methylbenzophenone (20 g, 102 mmol) dissolved in 40 mL of 1,2-dibromoethane was heated to reflux. Over a period of about 3 hours a solution of 105 mmol of bromine dissolved in 6 mL of 1,2-dibromoethane was added to the refluxing solution. After the addition was complete the solution was allowed to cool to rt and diluted with 100 mL of dichloromethane. The organic layer was extracted with 1×25 mL of 1 N HCl, 2×15 mL of NaHCO₃ Solution, and 2×25 ML of brine. The organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was then distilled to afford the product, 16.5 g (60%) as an oil that solidified upon standing, b.p. 160° C. at 300 mTorr. ¹H NMR analysis shows that the product contains approximately 7% of the dibromide.

3-(1,1-dimethylethylcarbomethoxy-N-(benzophenone-3-yl-methyl)caprolactam. Diisopropylamine (4.2 mL, 30 mmol) was dissolved in 25 mL of THF and chilled to −78° C. To the solution was added 10 mL of 2.5M n-butyllithium in hexanes and the solution was warmed to 0° C. and allowed to stir for 10 min. A solution of Boc-protected aminocaprolactam 1a (5.0 grams, 22 mmol) dissolved in 25 mL of THF was then added and the reaction solution was stirred for 1 h at 0° C. Solid 3-bromomethyl-benzophenone was then added and the reaction solution was allowed to warm to rt and stir overnight. The reaction solution was diluted with water and extracted into ethyl acetate (100 mL). The organic layer was rinsed with 2×25 mL of 1 N HCl, 2×25 mL of saturated NaHCO₃ and 2×25 mL of brine, dried over magnesium sulfate, and dried in vacuo. Chromatography eluting with a gradient of 30% to 40% ethyl acetate in hexanes afforded the pure benzophenone-substituted caprolactam derivative (7.4 g, 80%). MS (M+Na)⁺=445.

The compound of Example 10 was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 9 and the benzophenone-substituted caprolactam derivative. The compound was purified by crystallization from ethyl acetate to afford 0.26 g of crystals. MS (M+Na)+=540.

Example 38 (2R,3S)N1-[(3S)-hexahydro-1-(benzophenon-3-yl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

The compound of Example 11 was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 10 and the benzophenone-substituted caprolactam derivative. The compound was purified by crystallization from ethyl acetate to afford 0.25 g of crystals. MS (M+Na)+=542.

Example 39 (2R,3S)N1-[(3S)-hexahydro-1-(4-(4-trifluoromethylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide

(39-a) 3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam. The title compound was synthesized in a manner analogous to the preparation of 3-(1,1-dimethylethylcarbomethoxy-N-(benzophenone-3-yl-methyl)caprolactam in Example 10 but using 4-bromobenzyl bromide as the alkylaing agent. The compound was purified by chromatography eluting with 5-20% ethyl acetate in hexanes as eluent to provide 7.0 g (70%) of the title compound as a solid. MS (M+Na)+=419.

(39-b) 3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)phenylmethyl)caprolactam. To a solution of 3-(1,1-dimethylethylcarbomethoxy-N-(4-bromophenylmethyl)caprolactam (0.5 g, 1.26 mmol) dissolved in 10 mL of toluene was added 263 mg (1.38 mmol) of 4-trifluoromethylphenyl boronic acid, 1 mL of methanol, and 1 mL of a 2M solution of potassium carbonate. The solution was degassed by nitrogen bubbling for 5 min, and then 33 mg of tris(dibenzylideneacetone)dipalladium (0) chloroform adduct and 66 mg of triphenylphosphine was added. The solution ws heated to reflux for 16 h and then allowed to cool and diluted with 20 mL of water. The aqueous layer was extracted 3× with 25 mL of ethyla acetate and concentrated. The resulting oil was purified by chromatography eluting with 20% ethyl acetate in hexanes to afford 0.47 g (81%) of an oil which crystallized on standing.

(39-d) The compound 39-d was synthesized in a manner analagous to the synthesis of the compound of Example 8 using succinate 10 (280 mg, 1.04 mmol) and 3-(1,1-dimethylethylcarbomethoxy-N-(4,-(4′-trifluoromethylphenyl)-phenylmethyl)caprolactam. The compound was purified by chromatography eluting with 20-100% ethyl acetate in hexanes to afford 40 mg of a white powder. MS (M+H)+=560.

Example 40 (2S,3R)N1-[(3S)-hexahydro-1-(3-(2-tetrazolylphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide

(40-a) The compound of Example 40 was synthesized in a manner analogous to the synthesis of the compound of Example 39, but using the substituted acid 28 of Scheme 6 (50 mg, 0.10 mmol) and o-((N-trityl)-tetrazole)phenylboronic acid under the conditions for the formation of the compound (39-b). The desired biaryl acid was isolated as an impure mixture (134 mg) and used directly in the next step.

(40-b) The acid 40-a (134 mg, impure mixture) was converted to the amide under the conditions reported for the compound of Example 8. The crude amide was then dissolved in 2 mL of 10% trifluoroacetic acid in methanol and allowed to stir at rt for 30 min. The solvents were removed and the residue was purified by chromatography eluting with 10% methanol in ethyl acetate to provide 40 mg (71%, 2 steps) of the compound of Example 40 as a sticky powder. MS (M+Na)+=582.

Example 41 (2S,3R)N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(propyl)-3-(2-methylpropyl)-butanediamide

(41-a) The compound of Example 41 is formed by coupling Succinate 23 (480 mg, 1.21 mmol) with the substituted caprolactam TFA salt 2c under the conditions reported for the synthesis of the compound of Example 8. The crude fluorenylmethyl ester was used in the next step with out further purification. MS (M+Na)+=709.

(41-b) The crude fluorenylmethyl ester is dissolved in 2 mL of a 50% solution of piperidine in CH₂Cl₂ and stirred for 3 h at rt. A 10 mL portion of 1N HCl was then added and the mixture was extracted 3× with 10 mL of ethyl acetate. The crude acid was used in the next step with out further purification. MS (M+H)⁺=509.

The compound of Example 41 was then prepared using the acid 41-b under the conditions reported for compound of Example 28. The compound was purified by chromatography eluting with 5% methanol in CH₂Cl₂ to afford 120 mg (19%, 3 steps) of a white powder. MS (M+H)+=508.

Example 42 (2S,3R)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide

3-Phenoxybenzyl iodide: To a solution of 3-phenoxybenzyl chloride (10.0 g, 45.7 mmol) in 200 ml acetone was added sodium iodide (7.6 g, 507 mmol). The mixture was stirred at temperature overnight. The mixture was diluted with 300 ml hexane and the organic layer was washed twice with 5% sodium bicarbonate, once with brine and then dried over MgSO₄. Evaporation of the filtrate gave a light yellow oil. The product was used in next step without purification. ¹H NMR (CDCl₃) 4.4 (s,2H), 6.8-7.4 (m, 9H).

Synthesis of Example 42

To a solution of benzodiazepine 50 (910 mg, 3.63 mmol), succinate 9 (980 mg, 3.63 mmol), hydroxybenzotriazole (980 mg., 7.25 mmol) and EDC (870 mg, 4.54 mmol) in 100 ml CH₂Cl₂ at 0 degrees was added triethylamine (0.76 ml, 5.45 mmol). The reaction mixture was washed with saturated sodium bicarbonate solution, 1.0N HCl, brine and dried over MgSO₄. Evaporation of the organic layer and purification by column chromatography on silica gel with hexane-ethyl acetate (7:3) gave 610 mg of benzodiazepine 51 as a white solid. M+H=504.37. ¹H NMR (CDCl₃) 0.8-1.0 (m, 6H), 1.0-1.2 (m, 1H), 1.4-1.5 (d, 9H), 1.6-1.9 (m, 2H), 2.2-2.8 (m, 4H), 4.9-5.2 (m, 2H), 5.6 (dd, 1H), 5.6-6.0 (m, 1H), 7.0-7.6 (m, 9H).

To a solution of benzodiazepine 51 (440 mg, 0.875 mmol) in DMF (20 ml) at 0 degrees was added NaH (45 mg, 1.12 mmol). The mixture was stirred at 0 degrees for 1.5 hr and then a solution of 3-phenoxylbenzyl iodide (330 mg, 1.06 mmol) in 10 ml DMF was added dropwise. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC using hexanes:EtOAc 6:4 (product Rf=0.31) indicated that the reaction was complete. The reaction mixture was quenched with water, and the solvent was evaporated under high vacuum, which provided a viscous yellow oil. The product benzodiazepine 52 was dissolved in ethyl acetate, which was washed with water (2×), brine and then dried over MgSO₄.

Evaporation of solvent gave 600 mg of benzodiazepine 52 as a yellow oil which was not further purified. M+H=686.3, M+Na=708.3. ¹H NMR (CDCl₃) 0.8-1.0 (m, 6H), 1.0-1.3 (m, 1H), 1.4-1.5 (d, 9H), 1.5-1.9 (2H), 2.2-2.7 (4H), 4.6-4.8 (d,1H), 4.9-5.2 (m, 2H), 5.6-5.9 (m, 3H), 6.6-7.6 (m, 18H).

A solution of benzodiazepine 52 in 40 ml of TFA/CH₂Cl₂ (1:1) was stirred overnight at room temperature then evaporated to dryness. Repeated addition of toluene and evaporation provided 560 mg. of 53 as a yellow solid. (M−H=629.1)

To a solution of benzodiazepine 53 and HATU (410 mg, 1.08 mmol) in 30 ml DMF was added diisopropylethylamine (0.6 ml, 3.44 mmol) at 0 degrees. After 10 minutes, ammonia gas was bubbled through the solution for two minutes, and the reaction mixture was allowed to warm to room temperature and stirred overnight. Addition of water and solvent evaporation under high vacuum provided a yellow solid. The solid was taken up in ethyl acetate-water (1:1), and the organic layer was washed with water (2×), brine and then dried over MgSO₄. Evaporation of solvent gave a light yellow solid. Chromatographic purification on silica gel using CH₂Cl₂:methanol (10:0.5) gave 256 mg of Example 42. M+H=629.2 HNMR (CDCl₃) 0.8-1.0 (m, 6H), 1.2-1.4 (m, 1H), 1.6-2.0 (m, 2H), 2.2-2.8(4H), 4.6-4.8 (m, 1H), 5.0-0.2(m, 2H), 5.6-5.9 (m, 3H), 6.2-7.8 (m, 18H).

Example 43 (2R) N1-[(3S)-hexahydro-1-(3-phenoxybenzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-butanediamide

Step (43a): The compound of Step (43a) is formed by coupling succinate 7 (115 mg, 0.5 mmol) with the substituted caprolactam TFA salt (212 mg, 0.5 mmol) from Step (2c) of Example 2 under the conditions reported for the synthesis of the compound of Example 8. The crude tert-butyl ester was taken on without further purification.

Step (43b): The compound of Step (43b) is formed by dissolving the crude product from Step (43a) in 5 mL of a 1:1 solution of TFA/CH₂Cl₂ and stirring at room temperature for 2 hours. Concentration followed by reconcentration twice from 10 mL of toluene provides the crude acid which was taken on with no further purification.

Step (43c): The title compound, Example 43, was prepared using the acid from Step (43b) under the conditions reported for the compound of Example 7. The compound was purified by chromatography eluting with 5% methanol in CH₂Cl₂ to afford 50 mg (21%, 3 steps) of a white powder. MS (M+Na)⁺=488.

UTILITY

Aβ production has been implicated in the pathology of Alzheimer's Disease (AD). The compounds of the present invention have utility for the prevention and treatment of AD by inhibiting Aβ production. Methods of treatment target formation of Aβ production through the enzymes involved in the proteolytic processing of β-amyloid precursor protein. Compounds that inhibit b or g secretase activity, either directly or indirectly, control the production of Aβ. Such inhibition of β or γ secretases reduces production of Aβ, and is expected to reduce or prevent the neurological disorders associated with Aβ protein, such as Alzheimer's Disease.

Cellular screening methods for inhibitors of Aβ production, testing methods for the in vivo suppression of Aβ production, and assays for the detection of secretase activity are known in the art and have been disclosed in numerous publications, including PCT publication number WO 98/22493, EPO publication number 0652009, U.S. Pat. No. 5,703,129 and U.S. Pat. No. 5,593,846; all hereby incorporated by reference.

The compounds of the present invention have utility for the prevention and treatment of disorders involving Aβ production, such as cerebrovascular disorders.

Compounds of the present invention have been shown to inhibit Aβ production, as determined by the secretase inhibition assay described below.

Compounds of the present invention have been shown to inhibit Aβ production, utilizing the C-terminus b amyloid precursor protein accumulation assay described below.

Compounds of Formula (I) are expected to possess γ-secretase inhibitory activity. The γ-secretase inhibitory activity of the compounds of the present invention is demonstrated using assays for such activity, for Example, using the assay described below. Compounds of the present invention have been shown to inhibit the activity of γ-secretase, as determined by the Aβ immunoprecipitation assay.

Compounds provided by this invention should also be useful as standards and reagents in determining the ability of a potential pharmaceutical to inhibit Aβ production. These would be provided in commercial kits comprising a compound of this invention.

As used herein “μg” denotes microgram, “mg” denotes milligram, “g” denotes gram, “μL” denotes microliter, “mL” denotes milliliter, “L” denotes liter, “nM” denotes nanomolar, “μM” denotes micromolar, “mM” denotes millimolar, “M” denotes molar, “nm” denotes nanometer, “SDS” denotes sodium dodecyl sulfate, and “DMSO” denotes dimethyl sulfoxide, and “EDTA” denotes ethylenediaminetetraacetato.

A compound is considered to be active if it has an IC₅₀ or K_(i) value of less than about 100 μM for the inhibition of Aβ production or inhibition of proteolytic activity leading to Aβ production. Compounds, as demonstrated by use of the invention, have demonstrated IC₅₀ values, for the inhibition of Aβ production, of less than about 100 μM. Preferably compounds, as demonstrated by use of the invention, demonstrate IC₅₀ values, for the inhibition of Aβ production, of less than about 1 μM. More preferably compounds, as demonstrated by use of the invention, demonstrate IC₅₀ values, for the inhibition of Aβ production, of less than about 100 nM. Even more preferably compounds, as demonstrated by use of the invention, demonstrate IC₅₀ values, for the inhibition of Aβ production, of less than about 50 nM.

β Amyloid Precursor Protein Accumulation Assay (βAPPA Assay)

An assay to evaluate the accumulation of Aβ protein was developed to detect potential inhibitors of secretases. The assay uses the N 9 cell line, characterized for expression of exogenous APP by immunoblotting and immunoprecipitation.

The effect of test compounds on the accumulation of Aβ in the conditioned medium is tested by immunoprecipitation. N 9 cells are grown to confluency in 6-well plates and washed twice with 1×Hank's buffered salt solution. The cells are starved in methionine/cysteine deficient media for 30 min., followed by replacement with fresh deficient media containing 150 uCi Tran35S-LABEL™ (ICN). Test compounds dissolved in DMSO (final concentration 1%) are added, over a range of 1 picomolar to 100 micromolar, together with the addition of the fresh media containing Tran35S-LABEL™. The cells are incubated for 4 h at 37° C. in a tissue culture incubator.

At the end of the incubation period, the conditioned medium is harvested and pre-cleared by the addition of 5 μl normal mouse serum and 50 μl of protein A Sepharose (Pharmacia), mixed by end-over-end rotation for 30 minutes at 4^(O)C, followed by a brief centrifugation in a microfuge. The supernatant is then harvested and transferred to fresh tubes containing 5 ug of a monoclonal antibody (examples of antibodies include but are not limited by, clone 1101.1, directed against an internal peptide sequence in Aβ; or 6E10 from Senetek; or 4G8 from Senetek; additionally polyclonals from rabbit antihuman Aβ from Boehringer Mannheim) and 50 μl protein A Sepharose. After incubation overnight at 4^(O)C, the samples are washed three times with high salt washing buffer (50 mM Tris, pH 7.5, 500 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), three times with low salt wash buffer (50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM EDTA, 0.5% Nonidet P-40), and three times with 10 mM Tris, pH 7.5. The pellet after the last wash is resuspended in SDS sample buffer (Laemmli U.K. Cleavage of structural proteins during the assembly of the head of bacteriphage T4. Nature 227, 680-5, 1970.) and boiled for 3 minutes. The supernatant is then fractionated on either 10-20% Tris/Tricine SDS gels or on 16.5% Tris/Tricine SDS gels. The gels are dried and exposed to X-ray film or analyzed by phosphorimaging. The resulting image is analyzed for the presence of Aβ polypeptides. The steady-state level of Aβ in the presence of a test compound is compared to wells treated with DMSO (1%) alone. A typical test compound in this assay blocks Aβ accumulation in the conditioned medium, and is considered active with an IC₅₀ less than 100 μM.

C-Terminus β-Amyloid Precursor Protein Accumulation Assay (CTF Assay)

The effect of test compounds on the accumulation of C-terminal fragments is determined by immunoprecipitation of APP and fragments thereof from cell lysates. N 9 cells are metabolically labeled, as above, with media containing Tran35S-LABEL™, in the presence or absence of test compounds. At the end of the incubation period, the conditioned medium are harvested and cells lysed in RIPA buffer (10 mM Tris, pH 8.0 containing 1% Triton X-100, 1% deoxycholate, 0.1% SDS, 150 mM NaCl, 0.125% NaN₃). Again, lysates are precleared with 5 ul normal rabbit serum/50 ul protein A Sepharose, followed by the addition of BC-1 antiserum (15 μl) and 50 μl protein A Sepharose for 16 hours at 4^(O)C. The immunoprecipitates are washed as above, bound proteins eluted by boiling in SDS sample buffer and fractionated by Tris/Tricine SDS-PAGE. After exposure to X-ray film or phosphorimager, the resulting images are analyzed for the presence of C-terminal APP fragments. The steady-state level of C-terminal APP fragments is compared to wells treated with DMSO (1%) alone. A typical test compound in this assay stimulates C-terminal fragment accumulation in the cell lysates, and is considered active with an IC₅₀ less than 100 μM.

Accumulation-Release Assay

This immunoprecipitation assay is specific for g secretase activity (i.e., proteolytic activity required to generate the C-terminal end of Aβ either by direct cleavage or generating a C-terminal extended species which is subsequently further proteolyzed). N 9 cells are pulse labeled with media containing Tran35S-LABEL™ in the presence of a reported g secretase inhibitor (MDL 28170; Higaki J, Quon D, Zhong Z, Cordell B. Inhibition of beta-amyloid formation identifies proteolytic precursors and subcellular site of catabolism. Neuron 14, 651-659, 1995) for 1 h, followed by washing to remove ³⁵S radiolabel and MDL 28170. The media is replaced and test compounds are added over a dose range (for example 0.1 nM to 100 uM). The cells are chased for increasing periods of times and Aβ is isolated from the conditioned medium and C-terminal fragments from cell lysates (see accumulation assay above). The activity of test compounds are characterized by whether a stabilization of C-terminal fragments is observed and whether Aβ is generated from these accumulated precursor. A typical test compound in this assay prevents the generation of Aβ out of accumulated C-terminal fragments and is considered active with an IC₅₀ less than 100 μM.

Dosage and Formulation

The compounds determined from the present invention can be administered orally using any pharmaceutically acceptable dosage form known in the art for such administration. The active ingredient can be supplied in solid dosage forms such as dry powders, granules, tablets or capsules, or in liquid dosage forms, such as syrups or aqueous suspensions. The active ingredient can be administered alone, but is generally administered with a pharmaceutical carrier. A valuable treatise with respect to pharmaceutical dosage forms is Remington's Pharmaceutical Sciences, Mack Publishing.

The compounds determined from the present invention can be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may also be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed to prevent or treat neurological disorders related to β-amyloid production or accumulation, such as Alzheimer's disease and Down's Syndrome.

The compounds of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a host, such as a human or a mammal. They can be administered by any conventional means available for use in conjunction with pharmaceuticals, either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage regimen for the compounds determined from the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the species, age, sex, health, medical condition, and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; the route of administration, the renal and hepatic function of the patient, and the effect desired. An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter, or arrest the progress of the condition.

Advantageously, compounds determined from the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three, or four times daily.

The compounds identified using the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches wall known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittant throughout the dosage regimen.

In the methods of the present invention, the compounds herein described in detail can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as carrier materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; for oral administration in liquid form, the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents, and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or β-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.

The compounds determined from the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamallar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the compounds determined from the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers of hydrogels.

Gelatin capsules may contain the active ingredient and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance. In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.

The Tables below provide representative Examples of compounds of Formula (I) of the present invention. TABLE 1

Ex # R¹ R² R³ Z—Y—X—W 1 H OH propyl 3,3-diphenylpropyl 2 H OH propyl 3-phenoxybenzyl 3 H OH propyl phenyl 4 H CH₃ propyl 3-phenoxybenzyl 5 CH₃ OCH₃ propyl 3-phenoxybenzyl 6 H OCH₃ propyl 3-phenoxybenzyl 7 H H propyl 3-phenoxybenzyl 7A H NH₂ propyl 3-phenoxybenzyl 8 H H allyl 3-phenoxybenzyl 9 H OH allyl 3-phenoxybenzyl 10 H OH propyl 3-(2,4-dichlorophenyl)- benzyl 11 H OH propyl 3-(4-fluorophenyl)-benzyl 12 H OH propyl 3-(4-methylphenyl)-benzyl 13 H OH propyl 3-(4-methoxyphenyl)-benzyl 14 H OH propyl 3-(3-methyphenyl)-benzyl 15 H OH propyl 3-(3-chloro-4- fluorophenyl)-benzyl 16 H OH propyl 3-(4-trifluoromethyl- phenyl)benzyl 17 H OH propyl 3-(3-methoxyphenyl)-benzyl 18 H OH propyl 3-(3-fluorophenyl)-benzyl 19 H OH propyl 3-(2-methoxyphenyl)-benzyl 20 H OH propyl 3-(2-naphthyl)benzyl 21 H H propyl 3-(4-methoxyphenyl)-benzyl 22 H H propyl 3-(3-fluorophenyl)-benzyl 23 H H propyl 3-(4-F₃C-phenyl)benzyl 24 H H propyl 3-(2,4-Cl₂-phenyl)benzyl 25 H H propyl 3-(4-H₃C-phenyl)benzyl 26 H H propyl 3-(4-H₃CO-phenyl)benzyl 27 H H propyl 3-(3-Cl,4-F-phenyl)-benzyl 28 H H propyl 3-(3-H₃CO-phenyl)benzyl 29 H H propyl 3-(2-H₃CO-phenyl)benzyl 30 H H propyl 3-(4-H₃CO-phenyl)-pyrid-5- ylmethyl 31 H H propyl 3-(4-F₃C-phenyl)-pyrid-5- ylmethyl 32 H H propyl 3-(3-Cl,4-F-phenyl)-pyrid- 5-ylmethyl 33 H n-butyl propyl 3-phenoxybenzyl 34 H 2- propyl 3-phenoxybenzyl furyl- methyl 35 H C₅H₉ propyl 3-phenoxybenzyl 36 H cinnamyl propyl 3-phenoxybenzyl 37 H H allyl benzophenone-3-yl-methyl 38 H H propyl benzophenone-3-yl-methyl 39 H H propyl 4-(4-F₃C-phenyl)benzyl 40* H H i-butyl 3-(2-tetrazolyl-phenyl)- R⁵ = propyl benzyl 41* H H i-butyl 3-phenoxybenzyl R⁵ = propyl 43 H H H 3-phenoxybenzyl * For these compounds the i-butyl substituent on the carbon adjacent to CR³ in the captioned figure is actually n-propyl.

Table 2 demonstrates representative compounds envisaged within the scope of the present invention. Each formulae at the start of Table 2 are intended to be paired with each entry in the table which follows.

For example the compound (2R,3S)N1-[(3S)-hexahydro-1-(3-(3,4-dimethoxyphenyl)benzyl)-2-oxo-1H-azepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide is represented by Example #139-A-j, which comprises the core A, succinate j, and entry #139.

For example the compound (2R,3S)N1-[6,7-dihydro-5-(3-(3,4-dimethoxyphenyl)benzyl)-6-oxo-5H-dibenz[b,d]azepin-7-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide is represented by Example #139-B-j, which comprises the core B, succinate j, and entry #139.

For example the compound (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3,4-dimethoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide, is represented by Example #139-C-ab, which comprises the core C, succinate ab, and entry #139. TABLE 2

A

B

C

D

E

F

G

H

J

K Ex # W X Y Z 100 —CH₂— phen-1,3-diyl bond phenyl 101 —CH₂— phen-1,3-diyl bond 3,3- diphenylmethyl 102 —CH₂— phen-1,3-diyl bond 2-F-phenyl 103 —CH₂— phen-1,3-diyl bond 3-F-phenyl 104 —CH₂— phen-1,3-diyl bond 4-F-phenyl 105 —CH₂— phen-1,3-diyl bond 2-Cl-phenyl 106 —CH₂— phen-1,3-diyl bond 3-Cl-phenyl 107 —CH₂— phen-1,3-diyl bond 4-Cl-phenyl 108 —CH₂— phen-1,3-diyl bond 2-Me-phenyl 109 —CH₂— phen-1,3-diyl bond 3-Me-phenyl 110 —CH₂— phen-1,3-diyl bond 4-Me-phenyl 111 —CH₂— phen-1,3-diyl bond 2-MeO-phenyl 112 —CH₂— phen-1,3-diyl bond 3-MeO-phenyl 113 —CH₂— phen-1,3-diyl bond 4-MeO-phenyl 114 —CH₂— phen-1,3-diyl bond 2-MeS-phenyl 115 —CH₂— phen-1,3-diyl bond 3-MeS-phenyl 116 —CH₂— phen-1,3-diyl bond 4-MeS-phenyl 117 —CH₂— phen-1,3-diyl bond 2-F₃C-phenyl 118 —CH₂— phen-1,3-diyl bond 3-F₃C-phenyl 119 —CH₂— phen-1,3-diyl bond 4-F₃C-phenyl 120 —CH₂— phen-1,3-diyl bond 2,3-diF-phenyl 121 —CH₂— phen-1,3-diyl bond 2,4-diF-phenyl 122 —CH₂— phen-1,3-diyl bond 2,5-diF-phenyl 123 —CH₂— phen-1,3-diyl bond 2,6-diF-phenyl 124 —CH₂— phen-1,3-diyl bond 3,4-diF-phenyl 125 —CH₂— phen-1,3-diyl bond 3,5-diF-phenyl 126 —CH₂— phen-1,3-diyl bond 2,3-diCl-phenyl 127 —CH₂— phen-1,3-diyl bond 2,4-diCl-phenyl 128 —CH₂— phen-1,3-diyl bond 2,5-diCl-phenyl 129 —CH₂— phen-1,3-diyl bond 2,6-diCl-phenyl 130 —CH₂— phen-1,3-diyl bond 3,4-diCl-phenyl 131 —CH₂— phen-1,3-diyl bond 3,5-diCl-phenyl 132 —CH₂— phen-1,3-diyl bond 2-Cl-3-F-phenyl 133 —CH₂— phen-1,3-diyl bond 2-Cl-4-F-phenyl 134 —CH₂— phen-1,3-diyl bond 2-Cl-5-F-phenyl 135 —CH₂— phen-1,3-diyl bond 3-Cl-4-F-phenyl 136 —CH₂— phen-1,3-diyl bond 3-Cl-5-F-phenyl 137 —CH₂— phen-1,3-diyl bond 4-Cl-2-F-phenyl 138 —CH₂— phen-1,3-diyl bond 4-Cl-3-F-phenyl 139 —CH₂— phen-1,3-diyl bond 2,3-diMeO-phenyl 140 —CH₂— phen-1,3-diyl bond 2,4-diMeo-phenyl 141 —CH₂— phen-1,3-diyl bond 2,5-diMeO-phenyl 142 —CH₂— phen-1,3-diyl bond 2,6-diMeO-phenyl 143 —CH₂— phen-1,3-diyl bond 3,4-diMeO-phenyl 144 —CH₂— phen-1,3-diyl bond 3,5-diMeO-phenyl 145 —CH₂— phen-1,3-diyl bond cyclopropyl 146 —CH₂— phen-1,3-diyl bond cyclobutyl 147 —CH₂— phen-1,3-diyl bond cyclopentyl 148 —CH₂— phen-1,3-diyl bond cyclohexyl 149 —CH₂— phen-1,3-diyl bond 2-furanyl 150 —CH₂— phen-1,3-diyl bond 2-thienyl 151 —CH₂— phen-1,3-diyl bond 2-imidazolyl 152 —CH₂— phen-1,3-diyl bond 2-pyridyl 153 —CH₂— phen-1,3-diyl bond 3-pyridyl 154 —CH₂— phen-1,3-diyl bond 4-pyridyl 155 —CH₂— phen-1,3-diyl bond N-morpholinyl 156 —CH₂— phen-1,3-diyl bond N-piperidinyl 157 —CH₂— phen-1,3-diyl bond 3-Me-2-pyridyl 158 —CH₂— phen-1,3-diyl bond 4-Me-2-pyridyl 159 —CH₂— phen-1,3-diyl bond 1-indolyl 160 —CH₂— phen-1,3-diyl bond 2-benzothienyl 161 —CH₂— phen-1,3-diyl bond 2-benzofuranyl 162 —CH₂— phen-1,3-diyl bond 1-benzimidazole 163 —CH₂— phen-1,3-diyl bond 2-naphthyl 164 —CH₂— pyridin-3,5-diyl bond phenyl 165 —CH₂— pyridin-3,5-diyl bond 3,3- diphenylmethyl 166 —CH₂— pyridin-3,5-diyl bond 2-F-phenyl 167 —CH₂— pyridin-3,5-diyl bond 3-F-phenyl 168 —CH₂— pyridin-3,5-diyl bond 4-F-phenyl 169 —CH₂— pyridin-3,5-diyl bond 2-Cl-phenyl 170 —CH₂— pyridin-3,5-diyl bond 3-Cl-phenyl 171 —CH₂— pyridin-3,5-diyl bond 4-Cl-phenyl 172 —CH₂— pyridin-3,5-diyl bond 2-Me-phenyl 173 —CH₂— pyridin-3,5-diyl bond 3-Me-phenyl 174 —CH₂— pyridin-3,5-diyl bond 4-Me-phenyl 175 —CH₂— pyridin-3,5-diyl bond 2-MeO-phenyl 176 —CH₂— pyridin-3,5-diyl bond 3-MeO-phenyl 177 —CH₂— pyridin-3,5-diyl bond 4-MeO-phenyl 178 —CH₂— pyridin-3,5-diyl bond 2-MeS-phenyl 179 —CH₂— pyridin-3,5-diyl bond 3-MeS-phenyl 180 —CH₂— pyridin-3,5-diyl bond 4-MeS-phenyl 181 —CH₂— pyridin-3,5-diyl bond 2-F₃C-phenyl 182 —CH₂— pyridin-3,5-diyl bond 3-F₃C-phenyl 183 —CH₂— pyridin-3,5-diyl bond 4-F₃C-phenyl 184 —CH₂— pyridin-3,5-diyl bond 2,3-diF-phenyl 185 —CH₂— pyridin-3,5-diyl bond 2,4-diF-phenyl 186 —CH₂— pyridin-3,5-diyl bond 2,5-diF-phenyl 187 —CH₂— pyridin-3,5-diyl bond 2,6-diF-phenyl 188 —CH₂— pyridin-3,5-diyl bond 3,4-diF-phenyl 189 —CH₂— pyridin-3,5-diyl bond 3,5-diF-phenyl 190 —CH₂— pyridin-3,5-diyl bond 2,3-diCl-phenyl 191 —CH₂— pyridin-3,5-diyl bond 2,4-diCl-phenyl 192 —CH₂— pyridin-3,5-diyl bond 2,5-diCl-phenyl 193 —CH₂— pyridin-3,5-diyl bond 2,6-diCl-phenyl 194 —CH₂— pyridin-3,5-diyl bond 3,4-diCl-phenyl 195 —CH₂— pyridin-3,5-diyl bond 3,5-diCl-phenyl 196 —CH₂— pyridin-3,5-diyl bond 2-Cl-3-F-phenyl 197 —CH₂— pyridin-3,5-diyl bond 2-Cl-4-F-phenyl 198 —CH₂— pyridin-3,5-diyl bond 2-Cl-5-F-phenyl 199 —CH₂— pyridin-3,5-diyl bond 3-Cl-4-F-phenyl 200 —CH₂— pyridin-3,5-diyl bond 3-Cl-5-F-phenyl 201 —CH₂— pyridin-3,5-diyl bond 4-Cl-2-F-phenyl 202 —CH₂— pyridin-3,5-diyl bond 4-Cl-3-F-phenyl 203 —CH₂— pyridin-3,5-diyl bond 2,3-diMeO-phenyl 204 —CH₂— pyridin-3,5-diyl bond 2,4-diMeO-phenyl 205 —CH₂— pyridin-3,5-diyl bond 2,5-diMeO-phenyl 206 —CH₂— pyridin-3,5-diyl bond 2,6-diMeO-phenyl 207 —CH₂— pyridin-3,5-diyl bond 3,4-diMeO-phenyl 208 —CH₂— pyridin-3,5-diyl bond 3,5-diMeO-phenyl 209 —CH₂— pyridin-3,5-diyl bond cyclopropyl 210 —CH₂— pyridin-3,5-diyl bond cyclobutyl 211 —CH₂— pyridin-3,5-diyl bond cyclopentyl 212 —CH₂— pyridin-3,5-diyl bond cyclohexyl 213 —CH₂— pyridin-3,5-diyl bond 2-furanyl 214 —CH₂— pyridin-3,5-diyl bond 2-thienyl 215 —CH₂— pyridin-3,5-diyl bond 2-imidazolyl 216 —CH₂— pyridin-3,5-diyl bond 2-pyridyl 217 —CH₂— pyridin-3,5-diyl bond 3-pyridyl 218 —CH₂— pyridin-3,5-diyl bond 4-pyridyl 219 —CH₂— pyridin-3,5-diyl bond N-morpholinyl 220 —CH₂— pyridin-3,5-diyl bond N-piperidinyl 221 —CH₂— pyridin-3,5-diyl bond 3-Me-2-pyridyl 222 —CH₂— pyridin-3,5-diyl bond 4-Me-2-pyridyl 223 —CH₂— pyridin-3,5-diyl bond 1-indolyl 224 —CH₂— pyridin-3,5-diyl bond 2-benzothienyl 225 —CH₂— pyridin-3,5-diyl bond 2-benzofuranyl 226 —CH₂— pyridin-3,5-diyl bond 1-benzimidazole 227 —CH₂— pyridin-3,5-diyl bond 2-naphthyl 228 —CH₂— pyridin-2,6-diyl bond phenyl 229 —CH₂— pyridin-2,6-diyl bond 3,3- diphenylmethyl 230 —CH₂— pyridin-2,6-diyl bond 2-F-phenyl 231 —CH₂— pyridin-2,6-diyl bond 3-F-phenyl 232 —CH₂— pyridin-2,6-diyl bond 4-F-phenyl 233 —CH₂— pyridin-2,6-diyl bond 2-Cl-phenyl 234 —CH₂— pyridin-2,6-diyl bond 3-Cl-phenyl 235 —CH₂— pyridin-2,6-diyl bond 4-Cl-phenyl 236 —CH₂— pyridin-2,6-diyl bond 2-Me-phenyl 237 —CH₂— pyridin-2,6-diyl bond 3-Me-phenyl 238 —CH₂— pyridin-2,6-diyl bond 4-Me-phenyl 239 —CH₂— pyridin-2,6-diyl bond 2-MeO-phenyl 240 —CH₂— pyridin-2,6-diyl bond 3-MeO-phenyl 241 —CH₂— pyridin-2,6-diyl bond 4-MeO-phenyl 242 —CH₂— pyridin-2,6-diyl bond 2-MeS-phenyl 243 —CH₂— pyridin-2,6-diyl bond 3-MeS-phenyl 244 —CH₂— pyridin-2,6-diyl bond 4-MeS-phenyl 245 —CH₂— pyridin-2,6-diyl bond 2-F₃C-phenyl 246 —CH₂— pyridin-2,6-diyl bond 3-F₃C-phenyl 247 —CH₂— pyridin-2,6-diyl bond 4-F₃C-phenyl 248 —CH₂— pyridin-2,6-diyl bond 2,3-diF-phenyl 249 —CH₂— pyridin-2,6-diyl bond 2,4-diF-phenyl 250 —CH₂— pyridin-2,6-diyl bond 2,5-diF-phenyl 251 —CH₂— pyridin-2,6-diyl bond 2,6-diF-phenyl 252 —CH₂— pyridin-2,6-diyl bond 3,4-diF-phenyl 253 —CH₂— pyridin-2,6-diyl bond 3,5-diF-phenyl 254 —CH₂— pyridin-2,6-diyl bond 2,3-diCl-phenyl 255 —CH₂— pyridin-2,6-diyl bond 2,4-diCl-phenyl 256 —CH₂— pyridin-2,6-diyl bond 2,5-diCl-phenyl 257 —CH₂— pyridin-2,6-diyl bond 2,6-diCl-phenyl 258 —CH₂— pyridin-2,6-diyl bond 3,4-diCl-phenyl 259 —CH₂— pyridin-2,6-diyl bond 3,5-diCl-phenyl 260 —CH₂— pyridin-2,6-diyl bond 2-Cl-3-F-phenyl 261 —CH₂— pyridin-2,6-diyl bond 2-Cl-4-F-phenyl 262 —CH₂— pyridin-2,6-diyl bond 2-Cl-5-F-phenyl 263 —CH₂— pyridin-2,6-diyl bond 3-Cl-4-F-phenyl 264 —CH₂— pyridin-2,6-diyl bond 3-Cl-5-F-phenyl 265 —CH₂— pyridin-2,6-diyl bond 4-Cl-2-F-phenyl 266 —CH₂— pyridin-2,6-diyl bond 4-Cl-3-F-phenyl 267 —CH₂— pyridin-2,6-diyl bond 2,3-diMeO-phenyl 268 —CH₂— pyridin-2,6-diyl bond 2,4-diMeO-phenyl 269 —CH₂— pyridin-2,6-diyl bond 2,5-diMeO-phenyl 270 —CH₂— pyridin-2,6-diyl bond 2,6-diMeO-phenyl 271 —CH₂— pyridin-2,6-diyl bond 3,4-diMeO-phenyl 272 —CH₂— pyridin-2,6-diyl bond 3,5-diMeQ-phenyl 273 —CH₂— pyridin-2,6-diyl bond cyclopropyl 274 —CH₂— pyridin-2,6-diyl bond cyclobutyl 275 —CH₂— pyridin-2,6-diyl bond cyclopentyl 276 —CH₂— pyridin-2,6-diyl bond cyclohexyl 277 —CH₂— pyridin-2,6-diyl bond 2-furanyl 278 —CH₂— pyridin-2,6-diyl bond 2-thienyl 279 —CH₂— pyridin-2,6-diyl bond 2-imidazolyl 280 —CH₂— pyridin-2,6-diyl bond 2-pyridyl 281 —CH₂— pyridin-2,6-diyl bond 3-pyridyl 282 —CH₂— pyridin-2,6-diyl bond 4-pyridyl 283 —CH₂— pyridin-2,6-diyl bond N-morpholinyl 284 —CH₂— pyridin-2,6-diyl bond N-piperidinyl 285 —CH₂— pyridin-2,6-diyl bond 3-Me-2-pyridyl 286 —CH₂— pyridin-2,6-diyl bond 4-Me-2-pyridyl 287 —CH₂— pyridin-2,6-diyl bond 1-indolyl 288 —CH₂— pyridin-2,6-diyl bond 2-benzothienyl 289 —CH₂— pyridin-2,6-diyl bond 2-benzofuranyl 290 —CH₂— pyridin-2,6-diyl bond 1-benzimidazole 291 —CH₂— pyridin-2,6-diyl bond 2-naphthyl 292 —CH₂— pyridin-2,4-diyl bond phenyl 293 —CH₂— pyridin-2,4-diyl bond 3,3- diphenylmethyl 294 —CH₂— pyridin-2,4-diyl bond 2-F-phenyl 295 —CH₂— pyridin-2,4-diyl bond 3-F-phenyl 296 —CH₂— pyridin-2,4-diyl bond 4-F-phenyl 297 —CH₂— pyridin-2,4-diyl bond 2-Cl-phenyl 298 —CH₂— pyridin-2,4-diyl bond 3-Cl-phenyl 299 —CH₂— pyridin-2,4-diyl bond 4-Cl-phenyl 300 —CH₂— pyridin-2,4-diyl bond 2-Me-phenyl 301 —CH₂— pyridin-2,4-diyl bond 3-Me-phenyl 302 —CH₂— pyridin-2,4-diyl bond 4-Me-phenyl 303 —CH₂— pyridin-2,4-diyl bond 2-MeO-phenyl 304 —CH₂— pyridin-2,4-diyl bond 3-MeO-phenyl 305 —CH₂— pyridin-2,4-diyl bond 4-MeO-phenyl 306 —CH₂— pyridin-2,4-diyl bond 2-MeS-phenyl 307 —CH₂— pyridin-2,4-diyl bond 3-MeS-phenyl 308 —CH₂— pyridin-2,4-diyl bond 4-MeS-phenyl 309 —CH₂— pyridin-2,4-diyl bond 2-F₃C-phenyl 310 —CH₂— pyridin-2,4-diyl bond 3-F₃C-phenyl 311 —CH₂— pyridin-2,4-diyl bond 4-F₃C-phenyl 312 —CH₂— pyridin-2,4-diyl bond 2,3-diF-phenyl 313 —CH₂— pyridin-2,4-diyl bond 2,4-diF-phenyl 314 —CH₂— pyridin-2,4-diyl bond 2,5-diF-phenyl 315 —CH₂— pyridin-2,4-diyl bond 2,6-diF-phenyl 316 —CH₂— pyridin-2,4-diyl bond 3,4-diF-phenyl 317 —CH₂— pyridin-2,4-diyl bond 3,5-diF-phenyl 318 —CH₂— pyridin-2,4-diyl bond 2 ,3-diCl-phenyl 319 —CH₂— pyridin-2,4-diyl bond 2,4-diCl-phenyl 320 —CH₂— pyridin-2,4-diyl bond 2,5-diCl-phenyl 321 —CH₂— pyridin-2,4-diyl bond 2,6-diCl-phenyl 322 —CH₂— pyridin-2,4-diyl bond 3,4-diCl-phenyl 323 —CH₂— pyridin-2,4-diyl bond 3,5-diCl-phenyl 324 —CH₂— pyridin-2,4-diyl bond 2-Cl-3-F-phenyl 325 —CH₂— pyridin-2,4-diyl bond 2-Cl-4-F-phenyl 326 —CH₂— pyridin-2,4-diyl bond 2-Cl-5-F-phenyl 327 —CH₂— pyridin-2,4-diyl bond 3-Cl-4-F-phenyl 328 —CH₂— pyridin-2,4-diyl bond 3-Cl-5-F-phenyl 329 —CH₂— pyridin-2,4-diyl bond 4-Cl-2-F-phenyl 330 —CH₂— pyridin-2,4-diyl bond 4-Cl-3-F-phenyl 331 —CH₂— pyridin-2,4-diyl bond 2,3-diMeO-phenyl 332 —CH₂— pyridin-2,4-diyl bond 2,4-diMeO-phenyl 333 —CH₂— pyridin-2,4-diyl bond 2,5-diMeO-phenyl 334 —CH₂— pyridin-2,4-diyl bond 2,6-diMeO-phenyl 335 —CH₂— pyridin-2,4-diyl bond 3,4-diMeO-phenyl 336 —CH₂— pyridin-2,4-diyl bond 3,5-diMeO-phenyl 337 —CH₂— pyridin-2,4-diyl bond cyclopropyl 338 —CH₂— pyridin-2,4-diyl bond cyclobutyl 339 —CH₂— pyridin-2,4-diyl bond cyclopentyl 340 —CH₂— pyridin-2,4-diyl bond cyclohexyl 341 —CH₂— pyridin-2,4-diyl bond 2-furanyl 342 —CH₂— pyridin-2,4-diyl bond 2-thienyl 343 —CH₂— pyridin-2,4-diyl bond 2-imidazolyl 344 —CH₂— pyridin-2,4-diyl bond 2-pyridyl 345 —CH₂— pyridin-2,4-diyl bond 3-pyridyl 346 —CH₂— pyridin-2,4-diyl bond 4-pyridyl 347 —CH₂— pyridin-2,4-diyl bond N-morpholinyl 348 —CH₂— pyridin-2,4-diyl bond N-piperidinyl 349 —CH₂— pyridin-2,4-diyl bond 3-Me-2-pyridyl 350 —CH₂— pyridin-2,4-diyl bond 4-Me-2-pyridyl 351 —CH₂— pyridin-2,4-diyl bond 1-indolyl 352 —CH₂— pyridin-2,4-diyl bond 2-benzothienyl 353 —CH₂— pyridin-2,4-diyl bond 2-benzofuranyl 354 —CH₂— pyridin-2,4-diyl bond 1-benzimidazole 355 —CH₂— pyridin-2,4-diyl bond 2-naphthyl 356 —CH₂— pyridin-4,2-diyl bond phenyl 357 —CH₂— pyridin-4,2-diyl bond 3,3- diphenylmethyl 358 —CH₂— pyridin-4,2-diyl bond 2-F-phenyl 359 —CH₂— pyridin-4,2-diyl bond 3-F-phenyl 360 —CH₂— pyridin-4,2-diyl bond 4-F-phenyl 361 —CH₂— pyridin-4,2-diyl bond 2-Cl-phenyl 362 —CH₂— pyridin-4,2-diyl bond 3-Cl-phenyl 363 —CH₂— pyridin-4,2-diyl bond 4-Cl-phenyl 364 —CH₂— pyridin-4,2-diyl bond 2-Me-phenyl 365 —CH₂— pyridin-4,2-diyl bond 3-Me-phenyl 366 —CH₂— pyridin-4,2-diyl bond 4-Me-phenyl 367 —CH₂— pyridin-4,2-diyl bond 2-MeO-phenyl 368 —CH₂— pyridin-4,2-diyl bond 3-MeO-phenyl 369 —CH₂— pyridin-4,2-diyl bond 4-MeO-phenyl 370 —CH₂— pyridin-4,2-diyl bond 2-MeS-phenyl 371 —CH₂— pyridin-4,2-diyl bond 3-MeS-phenyl 372 —CH₂— pyridin-4,2-diyl bond 4-MeS-phenyl 373 —CH₂— pyridin-4,2-diyl bond 2-F₃C-phenyl 374 —CH₂— pyridin-4,2-diyl bond 3-F₃C-phenyl 375 —CH₂— pyridin-4,2-diyl bond 4-F₃C-phenyl 376 —CH₂— pyridin-4,2-diyl bond 2,3-diF-phenyl 377 —CH₂— pyridin-4,2-diyl bond 2,4-diF-phenyl 378 —CH₂— pyridin-4,2-diyl bond 2,5-diF-phenyl 379 —CH₂— pyridin-4,2-diyl bond 2,6-diF-phenyl 380 —CH₂— pyridin-4,2-diyl bond 3,4-diF-phenyl 381 —CH₂— pyridin-4,2-diyl bond 3,5-diF-phenyl 382 —CH₂— pyridin-4,2-diyl bond 2,3-diCl-phenyl 383 —CH₂— pyridin-4,2-diyl bond 2,4-diCl-phenyl 384 —CH₂— pyridin-4,2-diyl bond 2,5-diCl-phenyl 385 —CH₂— pyridin-4,2-diyl bond 2,6-diCl-phenyl 386 —CH₂— pyridin-4,2-diyl bond 3,4-diCl-phenyl 387 —CH₂— pyridin-4,2-diyl bond 3,5-diCl-phenyl 388 —CH₂— pyridin-4,2-diyl bond 2-Cl-3-F-phenyl 389 —CH₂— pyridin-4,2-diyl bond 2-Cl-4-F-phenyl 390 —CH₂— pyridin-4,2-diyl bond 2-Cl-5-F-phenyl 391 —CH₂— pyridin-4,2-diyl bond 3-Cl-4-F-phenyl 392 —CH₂— pyridin-4,2-diyl bond 3-Cl-5-F-phenyl 393 —CH₂— pyridin-4,2-diyl bond 4-Cl-2-F-phenyl 394 —CH₂— pyridin-4,2-diyl bond 4-Cl-3-F-phenyl 395 —CH₂— pyridin-4,2-diyl bond 2,3-diMeO-phenyl 396 —CH₂— pyridin-4,2-diyl bond 2,4-diMeO-phenyl 397 —CH₂— pyridin-4,2-diyl bond 2,5-diMeO-phenyl 398 —CH₂— pyridin-4,2-diyl bond 2,6-diMeO-phenyl 399 —CH₂— pyridin-4,2-diyl bond 3,4-diMeO-phenyl 400 —CH₂— pyridin-4,2-diyl bond 3,5-diMeO-phenyl 401 —CH₂— pyridin-4,2-diyl bond cyclopropyl 402 —CH₂— pyridin-4,2-diyl bond cyclobutyl 403 —CH₂— pyridin-4,2-diyl bond cyclopentyl 404 —CH₂— pyridin-4,2-diyl bond cyclohexyl 405 —CH₂— pyridin-4,2-diyl bond 2-furanyl 406 —CH₂— pyridin-4,2-diyl bond 2-thienyl 407 —CH₂— pyridin-4,2-diyl bond 2-imidazolyl 408 —CH₂— pyridin-4,2-diyl bond 2-pyridyl 409 —CH₂— pyridin-4,2-diyl bond 3-pyridyl 410 —CH₂— pyridin-4,2-diyl bond 4-pyridyl 411 —CH₂— pyridin-4,2-diyl bond N-morpholinyl 412 —CH₂— pyridin-4,2-diyl bond N-piperidinyl 413 —CH₂— pyridin-4,2-diyl bond 3-Me-2-pyridyl 414 —CH₂— pyridin-4,2-diyl bond 4-Me-2-pyridyl 415 —CH₂— pyridin-4,2-diyl bond 1-indolyl 416 —CH₂— pyridin-4,2-diyl bond 2-benzothienyl 417 —CH₂— pyridin-4,2-diyl bond 2-benzofuranyl 418 —CH₂— pyridin-4,2-diyl bond 1-benzimidazole 419 —CH₂— pyridin-4,2-diyl bond 2-naphthyl 420 —CH₂— piperidin-1,3- bond phenyl diyl 421 —CH₂— piperidin-1,3- bond 3,3- diyl diphenylmethyl 422 —CH₂— piperidin-1,3- bond 2-F-phenyl diyl 423 —CH₂— piperidin-1,3- bond 3-F-phenyl diyl 424 —CH₂— piperidin-1,3- bond 4-F-phenyl diyl 425 —CH₂— piperidin-1,3- bond 2-Cl-phenyl diyl 426 —CH₂— piperidin-1,3- bond 3-Cl-phenyl diyl 427 —CH₂— piperidin-1,3- bond 4-Cl-phenyl diyl 428 —CH₂— piperidin-1,3- bond 2-Me-phenyl diyl 429 —CH₂— piperidin-1,3- bond 3-Me-phenyl diyl 430 —CH₂— piperidin-1,3- bond 4-Ne-phenyl diyl 431 —CH₂— piperidin-1,3- bond 2-MeO-phenyl diyl 432 —CH₂— piperidin-1,3- bond 3-MeO-phenyl diyl 433 —CH₂— piperidin-1,3- bond 4-MeO-phenyl diyl 434 —CH₂— piperidin-1,3- bond 2-MeS-phenyl diyl 435 —CH₂— piperidin-1,3- bond 3-MeS-phenyl diyl 436 —CH₂— piperidin-1,3- bond 4-MeS-phenyl diyl 437 —CH₂— piperidin-1,3- bond 2-F₃C-phenyl diyl 438 —CH₂— piperidin-1,3- bond 3-F₃C-phenyl diyl 439 —CH₂— piperidin-1,3- bond 4-F₃C-phenyl diyl 440 —CH₂— piperidin-1,3- bond 2,3-diF-phenyl diyl 441 —CH₂— piperidin-1,3- bond 2,4-diF-phenyl diyl 442 —CH₂— piperidin-1,3- bond 2,5-diF-phenyl diyl 443 —CH₂— piperidin-1,3- bond 2,6-diF-phenyl diyl 444 —CH₂— piperidin-1,3- bond 3,4-diF-phenyl diyl 445 —CH₂— piperidin-1,3- bond 3,5-diF-phenyl diyl 446 —CH₂— piperidin-1,3- bond 2,3-diCl-phenyl diyl 447 —CH₂— piperidin-1,3- bond 2,4-diCl-phenyl diyl 448 —CH₂— piperidin-1,3- bond 2,5-diCl-phenyl diyl 449 —CH₂— piperidin-1,3- bond 2,6-diCl-phenyl diyl 450 —CH₂— piperidin-1,3- bond 3,4-diCl-phenyl diyl 451 —CH₂— piperidin-1,3- bond 3,5-diCl-phenyl diyl 452 —CH₂— piperidin-1,3- bond 2-Cl-3-F-phenyl diyl 453 —CH₂— piperidin-1,3- bond 2-Cl-4-F-phenyl diyl 454 —CH₂— piperidin-1,3- bond 2-Cl-5-F-phenyl diyl 455 —CH₂— piperidin-1,3- bond 3-Cl-4-F-phenyl diyl 456 —CH₂— piperidin-1,3- bond 3-Cl-5-F-phenyl diyl 457 —CH₂— piperidin-1,3- bond 4-Cl-2-F-phenyl diyl 458 —CH₂— piperidin-1,3- bond 4-Cl-3-F-phenyl diyl 459 —CH₂— piperidin-1,3- bond 2,3-diMeO-phenyl diyl 460 —CH₂— piperidin-1,3- bond 2,4-diMeO-phenyl diyl 461 —CH₂— piperidin-1,3- bond 2,5-diMeO-phenyl diyl 462 —CH₂— piperidin-1,3- bond 2,6-diMeO-phenyl diyl 463 —CH₂— piperidin-1,3- bond 3,4-diMeO-phenyl diyl 464 —CH₂— piperidin-1,3- bond 3,5-diMeO-phenyl diyl 465 —CH₂— piperidin-1,3- bond cyclopropyl diyl 466 —CH₂— piperidin-1,3- bond cyclobutyl diyl 467 —CH₂— piperidin-1,3- bond cyclopentyl diyl 468 —CH₂— piperidin-1,3- bond cyclohexyl diyl 469 —CH₂— piperidin-1,3- bond 2-furanyl diyl 470 —CH₂— piperidin-1,3- bond 2-thienyl diyl 471 —CH₂— piperidin-1,3- bond 2-imidazolyl diyl 472 —CH₂— piperidin-1,3- bond 2-pyridyl diyl 473 —CH₂— piperidin-1,3- bond 3-pyridyl diyl 474 —CH₂— piperidin-1,3- bond 4-pyridyl diyl 475 —CH₂— piperidin-1,3- bond N-morpholinyl diyl 476 —CH₂— piperidin-1,3- bond N-piperidinyl diyl 477 —CH₂— piperidin-1,3- bond 3-Me-2-pyridyl diyl 478 —CH₂— piperidin-1,3- bond 4-Me-2-pyridyl diyl 479 —CH₂— piperidin-1,3- bond 1-indolyl diyl 480 —CH₂— piperidin-1,3- bond 2-benzothienyl diyl 481 —CH₂— piperidin-1,3- bond 2-benzofuranyl diyl 482 —CH₂— piperidin-1,3- bond 1-benzimidazole diyl 483 —CH₂— piperidin-1,3- bond 2-naphthyl diyl 484 —CH₂— piperidin-3,1- bond phenyl diyl 485 —CH₂— piperidin-3,1- bond 3,3- diyl diphenylmethyl 486 —CH₂— piperidin-3,1- bond 2-F-phenyl diyl 487 —CH₂— piperidin-3,1- bond 3-F-phenyl diyl 488 —CH₂— piperidin-3,1- bond 4-F-phenyl diyl 489 —CH₂— piperidin-3,1- bond 2-Cl-phenyl diyl 490 —CH₂— piperidin-3,1- bond 3-Cl-phenyl diyl 491 —CH₂— piperidin-3,1- bond 4-Cl-phenyl diyl 492 —CH₂— piperidin-3,1- bond 2-Me-phenyl diyl 493 —CH₂— piperidin-3,1- bond 3-Me-phenyl diyl 494 —CH₂— piperidin-3,1- bond 4-Me-phenyl diyl 495 —CH₂— piperidin-3,1- bond 2-MeO-phenyl diyl 496 —CH₂— piperidin-3,1- bond 3-MeO-phenyl diyl 497 —CH₂— piperidin-3,1- bond 4-MeO-phenyl diyl 498 —CH₂— piperidin-3,1- bond 2-MeS-phenyl diyl 499 —CH₂— piperidin-3,1- bond 3-MeS-phenyl diyl 500 —CH₂— piperidin-3,1- bond 4-MeS-phenyl diyl 501 —CH₂— piperidin-3,1- bond 2-F₃C-phenyl diyl 502 —CH₂— piperidin-3,1- bond 3-F₃C-phenyl diyl 503 —CH₂— piperidin-3,1- bond 4-F₃C-phenyl diyl 504 —CH₂— piperidin-3,1- bond 2,3-diF-phenyl diyl 505 —CH₂— piperidin-3,1- bond 2,4-diF-phenyl diyl 506 —CH₂— piperidin-3,1- bond 2,5-diF-phenyl diyl 507 —CH₂— piperidin-3,1- bond 2,6-diF-phenyl diyl 508 —CH₂— piperidin-3,1- bond 3,4-diF-phenyl diyl 509 —CH₂— piperidin-3,1- bond 3,5-diF-phenyl diyl 510 —CH₂— piperidin-3,1- bond 2,3-diCl-phenyl diyl 511 —CH₂— piperidin-3,1- bond 2 4-diCl-phenyl diyl 512 —CH₂— piperidin-3,1- bond 2,5-diCl-phenyl diyl 513 —CH₂— piperidin-3,1- bond 2,6-diCl-phenyl diyl 514 —CH₂— piperidin-3,1- bond 3,4-diCl-phenyl diyl 515 —CH₂— piperidin-3,1- bond 3,5-diCl-phenyl diyl 516 —CH₂— piperidin-3,1- bond 2-Cl-3-F-phenyl diyl 517 —CH₂— piperidin-3,1- bond 2-Cl-4-F-phenyl diyl 518 —CH₂— piperidin-3,1- bond 2-Cl-5-F-phenyl diyl 519 —CH₂— piperidin-3,1- bond 3-Cl-4-F-phenyl diyl 520 —CH₂— piperidin-3,1- bond 3-Cl-5-F-phenyl diyl 521 —CH₂— piperidin-3,1- bond 4-Cl-2-F-phenyl diyl 522 —CH₂— piperidin-3,1- bond 4-Cl-3-F-phenyl diyl 523 —CH₂— piperidin-3,1- bond 2,3-diMeO-phenyl diyl 524 —CH₂— piperidin-3,1- bond 2,4-diMeO-phenyl diyl 525 —CH₂— piperidin-3,1- bond 2,5-diMeO-phenyl diyl 526 —CH₂— piperidin-3,1- bond 2,6-diMeO-phenyl diyl 527 —CH₂— piperidin-311- bond 3,4-diMeO-phenyl diyl 528 —CH₂— piperidin-3,1- bond 3,5-diMeO-phenyl diyl 529 —CH₂— piperidin-3,1- bond cyclopropyl diyl 530 —CH₂— piperidin-3,1- bond cyclobutyl diyl 531 —CH₂— piperidin-3,1- bond cyclopentyl diyl 532 —CH₂— piperidin-3,1- bond cyclohexyl diyl 533 —CH₂— piperidin-3,1- bond 2-furanyl diyl 534 —CH₂— piperidin-3,1- bond 2-thienyl diyl 535 —CH₂— piperidin-3,1- bond 2-imidazolyl diyl 536 —CH₂— piperidin-3,1- bond 2-pyridyl diyl 537 —CH₂— piperidin-3,1- bond 3-pyridyl diyl 538 —CH₂— piperidin-3,1- bond 4-pyridyl diyl 539 —CH₂— piperidin-3,1- bond N-morpholinyl diyl 540 —CH₂— piperidin-3,1- bond N-piperidinyl diyl 541 —CH₂— piperidin-3,1- bond 3-Me-2-pyridyl diyl 542 —CH₂— piperidin-3,1- bond 4-Me-2-pyridyl diyl 543 —CH₂— piperidin-3,1- bond 1-indolyl diyl 544 —CH₂— piperidin-3,1- bond 2-benzothienyl diyl 545 —CH₂— piperidin-3,1- bond 2-benzofuranyl diyl 546 —CH₂— piperidin-3,1- bond 1-benzimidazole diyl 547 —CH₂— piperidin-3,1- bond 2-naphthyl diyl 548 —CH₂— cyclohex-1,3-diyl bond phenyl 549 —CH₂— cyclohex-1,3-diyl bond 3,3- diphenylmethyl 550 —CH₂— cyclohex-1,3-diyl bond 2-F-phenyl 551 —CH₂— cyclohex-1,3-diyl bond 3-F-phenyl 552 —CH₂— cyclohex-1,3-diyl bond 4-F-phenyl 553 —CH₂— cyclohex-1,3-diyl bond 2-Cl-phenyl 554 —CH₂— cyclohex-1,3-diyl bond 3-Cl-phenyl 555 —CH₂— cyclohex-1,3-diyl bond 4-Cl-phenyl 556 —CH₂— cyclohex-1,3-diyl bond 2-Me-phenyl 557 —CH₂— cyclohex-1,3-diyl bond 3-Me-phenyl 558 —CH₂— cyclohex-1,3-diyl bond 4-Me-phenyl 559 —CH₂— cyclohex-1,3-diyl bond 2-MeO-phenyl 560 —CH₂— cyclohex-1,3-diyl bond 3-MeO-phenyl 561 —CH₂— cyclohex-1,3-diyl bond 4-MeO-phenyl 562 —CH₂— cyclohex-1,3-diyl bond 2-MeS-phenyl 563 —CH₂— cyclohex-1,3-diyl bond 3-MeS-phenyl 564 —CH₂— cyclohex-1,3-diyl bond 4-MeS-phenyl 565 —CH₂— cyclohex-1,3-diyl bond 2-F₃C-phenyl 566 —CH₂— cyclohex-1,3-diyl bond 3-F₃C-phenyl 567 —CH₂— cyclohex-1,3-diyl bond 4-F₃C-phenyl 568 —CH₂— cyclohex-1,3-diyl bond 2,3-diF-phenyl 569 —CH₂— cyclohex-1,3-diyl bond 2,4-diF-phenyl 570 —CH₂— cyclohex-1,3-diyl bond 2,5-diF-phenyl 571 —CH₂— cyclohex-1,3-diyl bond 2,6-diF-phenyl 572 —CH₂— cyclohex-1,3-diyl bond 3,4-diF-phenyl 573 —CH₂— cyclohex-1,3-diyl bond 3,5-diF-phenyl 574 —CH₂— cyclohex-1,3-diyl bond 2,3-diCl-phenyl 575 —CH₂— cyclohex-1,3-diyl bond 2,4-diCl-phenyl 576 —CH₂— cyclohex-1,3-diyl bond 2,5-diCl-phenyl 577 —CH₂— cyclohex-1,3-diyl bond 2,6-diCl-phenyl 578 —CH₂— cyclohex-1,3-diyl bond 3,4-diCl-phenyl 579 —CH₂— cyclohex-1,3-diyl bond 3,5-diCl-phenyl 580 —CH₂— cyclohex-1,3-diyl bond 2-Cl-3-F-phenyl 581 —CH₂— cyclohex-1,3-diyl bond 2-Cl-4-F-phenyl 582 —CH₂— cyclohex-1,3-diyl bond 2-Cl-5-F-phenyl 583 —CH₂— cyclohex-1,3-diyl bond 3-Cl-4-F-phenyl 584 —CH₂— cyclohex-1,3-diyl bond 3-Cl-5-F-phenyl 585 —CH₂— cyclohex-1,3-diyl bond 4-Cl-2-F-phenyl 586 —CH₂— cyclohex-1,3-diyl bond 4-Cl-3-F-phenyl 587 —CH₂— cyclohex-1,3-diyl bond 2,3-diMeO-phenyl 588 —CH₂— cyclohex-1,3-diyl bond 2,4-diMeO-phenyl 589 —CH₂— cyclohex-1,3-diyl bond 2,5-diMeO-phenyl 590 —CH₂— cyclohex-1,3-diyl bond 2,6-diMeO-phenyl 591 —CH₂— cyclohex-1,3-diyl bond 3,4-diMeO-phenyl 592 —CH₂— cyclohex-1,3-diyl bond 3,5-diMeQ-phenyl 593 —CH₂— cyclohex-1,3-diyl bond cyclopropyl 594 —CH₂— cyclohex-1,3-diyl bond Cyclobutyl 595 —CH₂— cyclohex-1,3-diyl bond cyclopentyl 596 —CH₂— cyclohex-1,3-diyl bond cyclohexyl 597 —CH₂— cyclohex-1,3-diyl bond 2-furanyl 598 —CH₂— cyclohex-1,3-diyl bond 2-thienyl 599 —CH₂— cyclohex-1,3-diyl bond 2-imidazolyl 600 —CH₂— cyclohex-1,3-diyl bond 2-pyridyl 601 —CH₂— cyclohex-1,3-diyl bond 3-pyridyl 602 —CH₂— cyclohex-1,3-diyl bond 4-pyridyl 603 —CH₂— cyclohex-1,3-diyl bond N-morpholinyl 604 —CH₂— cyclohex-1,3-diyl bond N-piperidinyl 605 —CH₂— cyclohex-1,3-diyl bond 3-Me-2-pyridyl 606 —CH₂— cyclohex-1,3-diyl bond 4-Me-2-pyridyl 607 —CH₂— cyclohex-1,3-diyl bond 1-indolyl 608 —CH₂— cyclohex-1,3-diyl bond 2-benzothienyl 609 —CH₂— cyclohex-1,3-diyl bond 2-benzofuranyl 610 —CH₂— cyclohex-1,3-diyl bond l-benzimidazole 611 —CH₂— cyclohex-1,3-diyl bond 2-naphthyl 612 —CH₂— cyclopropan-1,2- bond phenyl diyl 613 —CH₂— Cyclopropan-1,2- bond 3,3- diyl diphenylmethyl 614 —CH₂— cyclopropan-1,2 bond 2-F-phenyl diyl 615 —CH₂— cyclopropan-1,2 bond 3-F-phenyl diyl 616 —CH₂— cyciopropan-1,2- bond 4-F-phenyl diyl 617 —CH₂— cyclopropan-1,2- bond 2-Cl-phenyl diyl 618 —CH₂— cyclopropan-1,2- bond 3-Cl-phenyl diyl 619 —CH₂— cyclopropan-1,2 bond 4-Cl-phenyl diyl 620 —CH₂— cyclopropan-1,2- bond 2-Me-phenyl diyl 621 —CH₂— cyclopropan-1,2- bond 3-Me-phenyl diyl 622 —CH₂— cyclopropan-1,2- bond 4-Me-phenyl diyl 623 —CH₂— cyclopropan-1,2- bond 2-MeO-phenyl diyl 624 —CH₂— cyclopropan-1,2- bond 3-MeO-phenyl diyl 625 —CH₂— cyclopropan-1,2- bond 4-MeO-phenyl diyl 626 —CH₂— cyclopropan-1,2- bond 2-MeS-phenyl diyl 627 —CH₂— cyclopropan-1,2- bond 3-MeS-phenyl diyl 628 —CH₂— cyclopropan-1,2- bond 4-MeS-phenyl diyl 629 —CH₂— cyclopropan-1,2- bond 2-F₃C-phenyl diyl 630 —CH₂— cyclopropan-1,2- bond 3-F₃C-phenyl diyl 631 —CH₂— cyclopropan-1,2- bond 4-F₃C-phenyl diyl 632 —CH₂— cyclopropan-1,2- bond 2,3-diF-phenyl diyl 633 —CH₂— cyclopropan-1,2- bond 2,4-diF-phenyl diyl 634 —CH₂— cyclopropan-1,2- bond 2,5-diF-phenyl diyl 635 —CH₂— cyclopropan-1,2- bond 2,6-diF-phenyl diyl 636 —CH₂— cyclopropan-1,2- bond 3,4-diF-phenyl diyl 637 —CH₂— cyclopropan-1,2- bond 3,5-diF-phenyl diyl 638 —CH₂— cyclopropan-1,2- bond 2,3-diCl-phenyl diyl 639 —CH₂— cyclopropan-1,2- bond 2,4-diCl-phenyl diyl 640 —CH₂— cyclopropan-1,2- bond 2,5-diCl-phenyl diyl 641 —CH₂— cyclopropan-1,2- bond 216-diCl-phenyl diyl 642 —CH₂— cyclopropan-1,2- bond 314-diCl-phenyl diyl 643 —CH₂— cyclopropan-1,2- bond 3,5-diCl-phenyl diyl 644 —CH₂— cyclopropan-1,2- bond 2-Cl-3-F-phenyl diyl 645 —CH₂— cyclopropan-1,2- bond 2-Cl-4-F-phenyl diyl 646 —CH₂— cyclopropan-1,2- bond 2-Cl-5-F-phenyl diyl 647 —CH₂— cyclopropan-1,2- bond 3-Cl-4-F-phenyl diyl 648 —CH₂— cyclopropan-1,2- bond 3-Cl-5-F-phenyl diyl 649 —CH₂— cyclopropan-1,2- bond 4-Cl-2-F-phenyl diyl 650 —CH₂— cyclopropan-1,2- bond 4-Cl-3-F-phenyl diyl 651 —CH₂— cyclopropan-1,2- bond 2,3-diMeO-phenyl diyl 652 —CH₂— cyclopropan-1,2- bond 2,4-diMeO-phenyl diyl 653 —CH₂— cyclopropan-1,2- bond 2,5-diMeO-phenyl diyl 654 —CH₂— cyclopropan-1,2- bond 2,6-diMeO-phenyl diyl 655 —CH₂— cyclopropan-1,2- bond 3,4-diMeO-phenyl diyl 656 —CH₂— cyclopropan-1,2- bond 3,5-diMeO-phenyl diyl 657 —CH₂— cyclopropan-1,2- bond cyclopropyl diyl 658 —CH₂— cyclopropan-1,2- bond cyclobutyl diyl 659 —CH₂— cyclopropan-1,2- bond cyclopentyl diyl 660 —CH₂— cyclopropan-1,2- bond cyclohexyl diyl 661 —CH₂— cyclopropan-1,2- bond 2-furanyl diyl 662 —CH₂— cyclopropan-1,2- bond 2-thienyl diyl 663 —CH₂— cyclopropan-1,2- bond 2-imidazolyl diyl 664 —CH₂— cyclopropan-1,2- bond 2-pyridyl diyl 665 —CH₂— cyclopropan-1,2- bond 3-pyridyl diyl 666 —CH₂— cyclopropan-1,2- bond 4-pyridyl diyl 667 —CH₂— cyclopropan-1,2- bond N-morpholinyl diyl 668 —CH₂— cyclopropan-1,2- bond N-piperidinyl diyl 669 —CH₂— cyclopropan-1,2- bond 3-Me-2-pyridyl diyl 670 —CH₂— cyclopropan-1,2- bond 4-Me-2-pyridyl diyl 671 —CH₂— cyclopropan-1,2- bond 1-indolyl diyl 672 —CH₂— cyclopropan-1,2- bond 2-benzothienyl diyl 673 —CH₂— cyclopropan-1,2- bond 2-benzofuranyl diyl 674 —CH₂— cyclopropan-1,2- bond 1-benzimidazole diyl 675 —CH₂— cyclopropan-1,2- bond 2-naphthyl diyl 676 —CH₂— cyclopentan-1,3- bond phenyl diyl 677 —CH₂— cyclopentan-1,3- bond 3,3- diyl diphenylmethyl 678 —CH₂— cyclopentan-1,3- bond 2-F-phenyl diyl 679 —CH₂— cyclopentan-1,3- bond 3-F-phenyl diyl 680 —CH₂— cyclopentan-1,3- bond 4-F-phenyl diyl 681 —CH₂— cyclopentan-1,3- bond 2-Cl-phenyl diyl 682 —CH₂— cyclopentan-1,3- bond 3-Cl-phenyl diyl 683 —CH₂— cyclopentan-1,3- bond 4-Cl-phenyl diyl 684 —CH₂— cyclopentan-1,3- bond 2-Me-phenyl diyl 685 —CH₂— cyclopentan-1,3- bond 3-Me-phenyl diyl 686 —CH₂— cyclopentan-1,3- bond 4-Me-phenyl diyl 687 —CH₂— cyclopentan-1,3- bond 2-MeO-phenyl diyl 688 —CH₂— cyclopentan-1,3- bond 3-Me0-phenyl diyl 689 —CH₂— cyclopentan-1,3- bond 4-MeO-phenyl diyl 690 —CH₂— cyclopentan-1,3- bond 2-MeS-phenyl diyl 691 —CH₂— cyclopentan-1,3- bond 3-MeS-phenyl diyl 692 —CH₂— cyclopentan-1,3- bond 4-MeS-phenyl diyl 693 —CH₂— cyclopentan-1,3- bond 2-F₃C-phenyl diyl 694 —CH₂— cyclopentan-1,3- bond 3-F₃C-phenyl diyl 695 —CH₂— cyclopentan-1,3- bond 4-F₃C-phenyl diyl 696 —CH₂— cyclopentan-1,3- bond 2,3-diF-phenyl diyl 697 —CH₂— cyclopentan-1,3- bond 2,4-diF-phenyl diyl 698 —CH₂— cyclopentan-1,3- bond 2,5-diF-phenyl diyl 699 —CH₂— cyclopentan-1,3- bond 2,6-diF-phenyl diyl 700 —CH₂— cyclopentan-1,3- bond 3,4-diF-phenyl diyl 701 —CH₂— cyclopentan-1,3- bond 35-diF-phenyl diyl 702 —CH₂— cyclopentan-1,3- bond 2,3-diCl-phenyl diyl 703 —CH₂— cyclopentan-1,3- bond 2,4-diCl-phenyl diyl 704 —CH₂— cyclopentan-1,3- bond 2,5-diCl-phenyl diyl 705 —CH₂— cyclopentan-1,3- bond 2,6-diCl-phenyl diyl 706 —CH₂— cyclopentan-1,3- bond 3,4-diCl-phenyl diyl 707 —CH₂— cyclopentan-1,3- bond 3,5-diCl-phenyl diyl 708 —CH₂— cyclopentan-1,3- bond 2-Cl-3-F-phenyl diyl 709 —CH₂— cyclopentan-1,3- bond 2-Cl-4-F-phenyl diyl 710 —CH₂— cyclopentan-1,3- bond 2-Cl-5-F-phenyl diyl 711 —CH₂— cyclopentan-1,3- bond 3-Cl-4-F-phenyl diyl 712 —CH₂— cyclopentan-1,3- bond 3-Cl-5-F-phenyl diyl 713 —CH₂— cyclopentan-1,3- bond 4-Cl-2-F-phenyl diyl 714 —CH₂— cyclopentan-1,3- bond 4-Cl-3-F-phenyl diyl 715 —CH₂— cyclopentan-1,3- bond 2,3-diMeQ-phenyl diyl 716 —CH₂— cyclopentan-1,3- bond 2,4-diMeO-phenyl diyl 717 —CH₂— cyclopentan-1,3- bond 2,5-diMeG-phenyl diyl 718 —CH₂— cyclopentan-1,3- bond 2,6-diMeO-phenyl diyl 719 —CH₂— cyclopentan-1,3- bond 3,4-diMeG-phenyl diyl 720 —CH₂— cyclopentan-1,3- bond 3,5-diMeO-phenyl diyl 721 —CH₂— cyclopentan-1,3- bond cyclopropyl diyl 722 —CH₂— cyclopentan-1,3- bond cyclobutyl diyl 723 —CH₂— cyclopentan-1,3- bond cyclopentyl diyl 724 —CH₂— cyclopentan-1,3- bond cyclohexyl diyl 725 —CH₂— cyclopentan-1,3- bond 2-furanyl diyl 726 —CH₂— cyclopentan-1,3- bond 2-thienyl diyl 727 —CH₂— cyclopentan-1,3- bond 2-imidazolyl diyl 728 —CH₂— cyclopentan-1,3- bond 2-pyridyl diyl 729 —CH₂— cyclopentan-1,3- bond 3-pyridyl diyl 730 —CH₂— cyclopentan-1,3- bond 4-pyridyl diyl 731 —CH₂— cyclopentan-1,3- bond N-morpholinyl diyl 732 —CH₂— cyclopentan-1,3- bond N-piperidinyl diyl 733 —CH₂— cyclopentan-1,3- bond 3-Me-2-pyridyl diyl 734 —CH₂— cyclopentan-1,3- bond 4-Me-2-pyridyl diyl 735 —CH₂— cyclopentan-1,3- bond 1-indolyl diyl 736 —CH₂— cyclopentan-1,3- bond 2-benzothienyl diyl 737 —CH₂— cyclopentan-1,3- bond 2-benzofuranyl diyl 738 —CH₂— cyclopentan-1,3- bond 1-benzimidazoie diyl 739 —CH₂— cyclopentan-1,3- bond 2-naphthyl diyl 740 —CH₂— phen-1,3-diyl —O— phenyl 741 —CH₂— phen-1,3-diyl —O— 3,3- diphenylmethyl 742 —CH₂— phen-1,3-diyl —O— 2-F-phenyl 743 —CH₂— phen-1,3-diyl —O— 3-F-phenyl 744 —CH₂— phen-1,3-diyl —O— 4-F-phenyl 745 —CH₂— phen-1,3-diyl —O— 2-Cl-phenyl 746 —CH₂— phen-1,3-diyl —O— 3-Cl-phenyl 747 —CH₂— phen-1,3-diyl —O— 4-Cl-phenyl 748 —CH₂— phen-1,3-diyl —O— 2-Me-phenyl 749 —CH₂— phen-1,3-diyl —O— 3-Me-phenyl 750 —CH₂— phen-1,3-diyl —O— 4-Me-phenyl 751 —CH₂— phen-1,3-diyl —O— 2-MeO-phenyl 752 —CH₂— phen-1,3-diyl —O— 3-MeO-phenyl 753 —CH₂— phen-1,3-diyl —O— 4-MeO-phenyl 754 —CH₂— phen-1,3-diyl —O— 2-MeS-phenyl 755 —CH₂— phen-1,3-diyl —O— 3-MeS-phenyl 756 —CH₂— phen-1,3-diyl —O— 4-MeS-phenyl 757 —CH₂— phen-1,3-diyl —O— 2-F₃C-phenyl 758 —CH₂— phen-1,3-diyl —O— 3-F₃C-phenyl 759 —CH₂— phen-1,3-diyl —O— 4-F₃C-phenyl 760 —CH₂— phen-1,3-diyl —O— 2,3-diF-phenyl 761 —CH₂— phen-1,3-diyl —O— 2,4-diF-phenyl 762 —CH₂— phen-1,3-diyl —O— 2,5-diF-phenyl 763 —CH₂— phen-1,3-diyl —O— 2,6-diF-phenyl 764 —CH₂— phen-1,3-diyl —O— 3 4-diF-phenyl 765 —CH₂— phen-1,3-diyl —O— 3,5-diF-phenyl 766 —CH₂— phen-1,3-diyl —O— 2,3-diCl-phenyl 767 —CH₂— phen-1,3-diyl —O— 2,4-diCl-phenyl 768 —CH₂— phen-1,3-diyl —O— 2,5-diCl-phenyl 769 —CH₂— phen-1,3-diyl —O— 2,6-diCl-phenyl 770 —CH₂— phen-1,3-diyl —O— 3,4-diCl-phenyl 771 —CH₂— phen-1,3-diyl —O— 3,5-diCl-phenyl 772 —CH₂— phen-1,3-diyl —O— 2-Cl-3-F-phenyl 773 —CH₂— phen-1,3-diyl —O— 2-Cl-4-F-phenyl 774 —CH₂— phen-1,3-diyl —O— 2-Cl-5-F-phenyl 775 —CH₂— phen-1,3-diyl —O— 3-Cl-4-F-phenyl 776 —CH₂— phen-1,3-diyl —O— 3-Cl-5-F-phenyl 777 —CH₂— phen-1,3-diyl —O— 4-Cl-2-F-phenyl 778 —CH₂— phen-1,3-diyl —O— 4-Cl-3-F-phenyl 779 —CH₂— phen-1,3-diyl —O— 2,3-diMeo-phenyl 780 —CH₂— phen-1,3-diyl —O— 2,4-diMeo-phenyl 781 —CH₂— phen-1,3-diyl —O— 2,5-diMeo-phenyl 782 —CH₂— phen-1,3-diyl —O— 2,6-diMeo-phenyl 783 —CH₂— phen-1,3-diyl —O— 3,4-diMeo-phenyl 784 —CH₂— phen-1,3-diyl —O— 3,5-diMeo-phenyl 785 —CH₂— phen-1,3-diyl —O— cyclopropyl 786 —CH₂— phen-1,3-diyl —O— cyclobutyl 787 —CH₂— phen-1,3-diyl —O— cyclopentyl 788 —CH₂— phen-1,3-diyl —O— cyclohexyl 789 —CH₂— phen-1,3-diyl —O— 2-furanyl 790 —CH₂— phen-1,3-diyl —O— 2-thienyl 791 —CH₂— phen-1,3-diyl CH₂CH₂ 2-imidazolyl 792 —CH₂— phen-1,3-diyl —O— 2-pyridyl 793 —CH₂— phen-1,3-diyl —O— 3-pyridyl 794 —CH₂— phen-1,3-diyl —O— 4-pyridyl 795 —CH₂— phen-1,3-diyl CH₂CH₂ N-morpholinyl 796 —CH₂— phen-1,3-diyl CH₂CH₂ N-piperidinyl 797 —CH₂— phen-1,3-diyl —O— 3-Me-2-pyridyl 798 —CH₂— phen-1,3-diyl —O— 4-Me-2-pyridyl 799 —CH₂— phen-1,3-diyl CH₂CH₂ 1-indolyl 800 —CH₂— phen-1,3-diyl —O— 2-benzothienyl 801 —CH₂— phen-1,3-diyl —O— 2-benzofuranyl 802 —CH₂— phen-1,3-diyl CH₂CH₂ 1-benzimidazole 803 —CH₂— phen-1,3-diyl —O— 2-naphthyl 804 —CH₂— pyridin-3,5-diyl —O— phenyl 805 —CH₂— pyridin-3,5-diyl —O— 3,3- diphenylmethyl 806 —CH₂— pyridin-3,5-diyl —O— 2-F-phenyl 807 —CH₂— pyridin-3,5-diyl —O— 3-F-phenyl 808 —CH₂— pyridin-3,5-diyl —O— 4-F-phenyl 809 —CH₂— pyridin-3,5-diyl —O— 2-Cl-phenyl 810 —CH₂— pyridin-3,5-diyl —O— 3-Cl-phenyl 811 —CH₂— pyridin-3,5-diyl —O— 4-Cl-phenyl 812 —CH₂— pyridin-3,5-diyl —O— 2-Me-phenyl 813 —CH₂— pyridin-3,5-diyl —O— 3-Me-phenyl 814 —CH₂— pyridin-3,5-diyl —O— 4-Me-phenyl 815 —CH₂— pyridin-3,5-diyl —O— 2-MeO-phenyl 816 —CH₂— pyridin-3,5-diyl —O— 3-MeO-phenyl 817 —CH₂— pyridin-3,5-diyl —O— 4-MeO-phenyl 818 —CH₂— pyridin-3,5-diyl —O— 2-MeS-phenyl 819 —CH₂— pyridin-3,5-diyl —O— 3-MeS-phenyl 820 —CH₂— pyridin-3,5-diyl —O— 4-MeS-phenyl 821 —CH₂— pyridin-3,5-diyl —O— 2-F₃C-phenyl 822 —CH₂— pyridin-3,5-diyl —O— 3-F₃C-phenyl 823 —CH₂— pyridin-3,5-diyl —O— 4-F₃C-phenyl 824 —CH₂— pyridin-3,5-diyl —O— 2,3-diF-phenyl 825 —CH₂— pyridin-3,5-diyl —O— 2,4-diF-phenyl 826 —CH₂— pyridin-3,5-diyl —O— 2,5-diF-phenyl 827 —CH₂— pyridin-3,5-diyl —O— 2,6-diF-phenyl 828 —CH₂— pyridin-3,5-diyl —O— 3,4-diF-phenyl 829 —CH₂— pyridin-3,5-diyl —O— 3,5-diF-phenyl 830 —CH₂— pyridin-3,5-diyl —O— 2,3-diCl-phenyl 831 —CH₂— pyridin-3,5-diyl —O— 2,4-diCl-phenyl 832 —CH₂— pyridin-3,5-diyl —O— 2,5-diCl-phenyl 833 —CH₂— pyridin-3,5-diyl —O— 2,6-diCl-phenyl 834 —CH₂— pyridin-3,5-diyl —O— 3,4-diCl-phenyl 835 —CH₂— pyridin-3,5-diyl —O— 3,5-diCl-phenyl 836 —CH₂— pyridin-3,5-diyl —O— 2-Cl-3-F-phenyl 837 —CH₂— pyridin-3,5-diyl —O— 2-Cl-4-F-phenyl 838 —CH₂— pyridin-3,5-diyl —O— 2-Cl-5-F-phenyl 839 —CH₂— pyridin-3,5-diyl —O— 3-Cl-4-F-phenyl 840 —CH₂— pyridin-3,5-diyl —O— 3-Cl-5-F-phenyl 841 —CH₂— pyridin-3,5-diyl —O— 4-Cl-2-F-phenyl 842 —CH₂— pyridin-3,5-diyl —O— 4-Cl-3-F-phenyl 843 —CH₂— pyridin-3,5-diyl —O— 2,3-diMeo-phenyl 844 —CH₂— pyridin-3,5-diyl —O— 2,4-diMeo-phenyl 845 —CH₂— pyridin-3,5-diyl —O— 2,5-diMeo-phenyl 846 —CH₂— pyridin-3,5-diyl —O— 2,6-diMeo-phenyl 847 —CH₂— pyridin-3,5-diyl —O— 3,4-diMeo-phenyl 848 —CH₂— pyridin-3,5-diyl —O— 3,5-diMeo-phenyl 849 —CH₂— pyridin-3,5-diyl —O— cyclopropyl 850 —CH₂— pyridin-3,5-diyl —O— cyclobutyl 851 —CH₂— pyridin-3,5-diyl —O— cyclopentyl 852 —CH₂— pyridin-3,5-diyl —O— cyclohexyl 853 —CH₂— pyridin-3,5-diyl —O— 2-furanyl 854 —CH₂— pyridin-3,5-diyl —O— 2-thienyl 855 —CH₂— pyridin-3,5-diyl CH₂CH₂ 2-imidazolyl 856 —CH₂— pyridin-3,5-diyl —O— 2-pyridyl 857 —CH₂— pyridin-3,5-diyl —O— 3-pyridyl 858 —CH₂— pyridin-3,5-diyl —O— 4-pyridyl 859 —CH₂— pyridin-3,5-diyl CH₂CH₂ N-morpholinyl 860 —CH₂— pyridin-3,5-diyl CH₂CH₂ N-piperidinyl 861 —CH₂— pyridin-3,5-diyl —O— 3-Me-2-pyridyl 862 —CH₂— pyridin-3,5-diyl —O— 4-Me-2-pyridyl 863 —CH₂— pyridin-3,5-diyl CH₂CH₂ 1-indolyl 864 —CH₂— pyridin-3,5-diyl —O— 2-benzothienyl 865 —CH₂— pyridin-3,5-diyl —O— 2-benzofuranyl 866 —CH₂— pyridin-3,5-diyl CH₂CH₂ 1-benzimidazole 867 —CH₂— pyridin-3,5-diyl —O— 2-naphthyl 868 —CH₂— pyridin-2,6-diyl —O— phenyl 869 —CH₂— pyridin-2,6-diyl —O— 3,3- diphenylmethyl 870 —CH₂— pyridin-2,6-diyl —O— 2-F-phenyl 871 —CH₂— pyridin-2,6-diyl —O— 3-F-phenyl 872 —CH₂— pyridin-2,6-diyl —O— 4-F-phenyl 873 —CH₂— pyridin-2,6-diyl —O— 2-Cl-phenyl 874 —CH₂— pyridin-2,6-diyl —O— 3-Cl-phenyl 875 —CH₂— pyridin-2,6-diyl —O— 4-Cl-phenyl 876 —CH₂— pyridin-2,6-diyl —O— 2-Me-phenyl 877 —CH₂— pyridin-2,6-diyl —O— 3-Me-phenyl 878 —CH₂— pyridin-2,6-diyl —O— 4-Me-phenyl 879 —CH₂— pyridin-2,6-diyl —O— 2-MeO-phenyl 880 —CH₂— pyridin-2,6-diyl —O— 3-MeO-phenyl 881 —CH₂— pyridin-2,6-diyl —O— 4-MeO-phenyl 882 —CH₂— pyridin-2,6-diyl —O— 2-MeS-phenyl 883 —CH₂— pyridin-2,6-diyl —O— 3-MeS-phenyl 884 —CH₂— pyridin-2,6-diyl —O— 4-MeS-phenyl 885 —CH₂— pyridin-2,6-diyl —O— 2-F₃C-phenyl 886 —CH₂— pyridin-2,6-diyl —O— 3-F₃C-phenyl 887 —CH₂— pyridin-2,6-diyl —O— 4-F₃C-phenyl 888 —CH₂— pyridin-2,6-diyl —O— 2,3-diF-phenyl 889 —CH₂— pyridin-2,6-diyl —O— 2,4-diF-phenyl 890 —CH₂— pyridin-2,6-diyl —O— 2,5-diF-phenyl 891 —CH₂— pyridin-2,6-diyl —O— 2,6-diF-phenyl 892 —CH₂— pyridin-2,6-diyl —O— 3,4-diF-phenyl 893 —CH₂— pyridin-2,6-diyl —O— 3,5-diF-phenyl 894 —CH₂— pyridin-2,6-diyl —O— 2,3-diCl-phenyl 895 —CH₂— pyridin-2,6-diyl —O— 2,4-diCl-phenyl 896 —CH₂— pyridin-2,6-diyl —O— 2,5-diCl-phenyl 897 —CH₂— pyridin-2,6-diyl —O— 2,6-diCl-phenyl 898 —CH₂— pyridin-2,6-diyl —O— 3,4-diCl-phenyl 899 —CH₂— pyridin-2,6-diyl —O— 3,5-diCl-phenyl 900 —CH₂— pyridin-2,6-diyl —O— 2-Cl-3-F-phenyl 901 —CH₂— pyridin-2,6-diyl —O— 2-Cl-4-F-phenyl 902 —CH₂— pyridin-2,6-diyl —O— 2-Cl-5-F-phenyl 903 —CH₂— pyridin-2,6-diyl —O— 3-Cl-4-F-phenyl 904 —CH₂— pyridin-2,6-diyl —O— 3-Cl-5-F-phenyl 905 —CH₂— pyridin-2,6-diyl —O— 4-Cl-2-F-phenyl 906 —CH₂— pyridin-2,6-diyl —O— 4-Cl-3-F-phenyl 907 —CH₂— pyridin-2,6-diyl —O— 2,3-diMeo-phenyl 908 —CH₂— pyridin-2,6-diyl —O— 2,4-diMeo-phenyl 909 —CH₂— pyridin-2,6-diyl —O— 2,5-diMeo-phenyl 910 —CH₂— pyridin-2,6-diyl —O— 2,6-diMeo-phenyl 911 —CH₂— pyridin-2,6-diyl —O— 3,4-diMeo-phenyl 912 —CH₂— pyridin-2,6-diyl —O— 3,5-diMeo-phenyl 913 —CH₂— pyridin-2,6-diyl —O— cyclopropyl 914 —CH₂— pyridin-2,6-diyl —O— cyclobutyl 915 —CH₂— pyridin-2,6-diyl —O— cyclopentyl 916 —CH₂— pyridin-2,6-diyl —O— cyclohexyl 917 —CH₂— pyridin-2,6-diyl —O— 2-furanyl 918 —CH₂— pyridin-2,6-diyl —O— 2-thienyl 919 —CH₂— pyridin-2,6-diyl CH₂CH₂ 2-imidazolyl 920 —CH₂— pyridin-2,6-diyl —O— 2-pyridyl 921 —CH₂— pyridin-2,6-diyl —O— 3-pyridyl 922 —CH₂— pyridin-2,6-diyl —O— 4-pyridyl 923 —CH₂— pyridin-2,6-diyl CH₂CH₂ N-morpholinyl 924 —CH₂— pyridin-2,6-diyl CH₂CH₂ N-piperidinyl 925 —CH₂— pyridin-2,6-diyl —O— 3-Me-2-pyridyl 926 —CH₂— pyridin-2,6-diyl —O— 4-Me-2-pyridyl 927 —CH₂— pyridin-2,6-diyl CH₂CH₂ 1-indolyl 928 —CH₂— pyridin-2,6-diyl —O— 2-benzothienyl 929 —CH₂— pyridin-2,6-diyl —O— 2-benzofuranyl 930 —CH₂— pyridin-2,6-diyl CH₂CH₂ 1-benzimidazole 931 —CH₂— pyridin-2,6-diyl —O— 2-naphthyl 932 —CH₂— pyridin-2,4-diyl —O— phenyl 933 —CH₂— pyridin-2,4-diyl —O— 3,3- diphenylmethyl 934 —CH₂— pyridin-2,4-diyl —O— 2-F-phenyl 935 —CH₂— pyridin-2,4-diyl —O— 3-F-phenyl 936 —CH₂— pyridin-2,4-diyl —O— 4-F-phenyl 937 —CH₂— pyridin-2,4-diyl —O— 2-Cl-phenyl 938 —CH₂— pyridin-2,4-diyl —O— 3-Cl-phenyl 939 —CH₂— pyridin-2,4-diyl —O— 4-Cl-phenyl 940 —CH₂— pyridin-2,4-diyl —O— 2-Me-phenyl 941 —CH₂— pyridin-2,4-diyl —O— 3-Me-phenyl 942 —CH₂— pyridin-2,4-diyl —O— 4-Me-phenyl 943 —CH₂— pyridin-2,4-diyl —O— 2-MeO-phenyl 944 —CH₂— pyridin-2,4-diyl —O— 3-MeO-phenyl 945 —CH₂— pyridin-2,4-diyl —O— 4-MeO-phenyl 946 —CH₂— pyridin-2,4-diyl —O— 2-MeS-phenyl 947 —CH₂— pyridin-2,4-diyl —O— 3-MeS-phenyl 948 —CH₂— pyridin-2,4-diyl —O— 4-MeS-phenyl 949 —CH₂— pyridin-2,4-diyl —O— 2-F₃C-phenyl 950 —CH₂— pyridin-2,4-diyl —O— 3-F₃C-phenyl 951 —CH₂— pyridin-2,4-diyl —O— 4-F₃C-phenyl 952 —CH₂— pyridin-2,4-diyl —O— 2,3-diF-phenyl 953 —CH₂— pyridin-2,4-diyl —O— 2,4-diF-phenyl 954 —CH₂— pyridin-2,4-diyl —O— 2,5-diF-phenyl 955 —CH₂— pyridin-2,4-diyl —O— 2,6-diF-phenyl 956 —CH₂— pyridin-2,4-diyl —O— 3,4-diF-phenyl 957 —CH₂— pyridin-2,4-diyl —O— 3,5-diF-phenyl 958 —CH₂— pyridin-2,4-diyl —O— 2,3-diCl-phenyl 959 —CH₂— pyridin-2,4-diyl —O— 2,4-diCl-phenyl 960 —CH₂— pyridin-2,4-diyl —O— 2,5-diCl-phenyl 961 —CH₂— pyridin-2,4-diyl —O— 2,6-diCl-phenyl 962 —CH₂— pyridin-2,4-diyl —O— 3,4-diCl-phenyl 963 —CH₂— pyridin-2,4-diyl —O— 3,5-diCl-phenyl 964 —CH₂— pyridin-2,4-diyl —O— 2-Cl-3-F-phenyl 965 —CH₂— pyridin-2,4-diyl —O— 2-Cl-4-F-phenyl 966 —CH₂— pyridin-2,4-diyl —O— 2-Cl-5-F-phenyl 967 —CH₂— pyridin-2,4-diyl —O— 3-Cl-4-F-phenyl 968 —CH₂— pyridin-2,4-diyl —O— 3-Cl-5-F-phenyl 969 —CH₂— pyridin-2,4-diyl —O— 4-Cl-2-F-phenyl 970 —CH₂— pyridin-2,4-diyl —O— 4-Cl-3-F-phenyl 971 —CH₂— pyridin-2,4-diyl —O— 2,3-diMeo-phenyl 972 —CH₂— pyridin-2,4-diyl —O— 2,4-diMeo-phenyl 973 —CH₂— pyridin-2,4-diyl —O— 2,5-diMeo-phenyl 974 —CH₂— pyridin-2,4-diyl —O— 2,6-diMeo-phenyl 975 —CH₂— pyridin-2,4-diyl —O— 3,4-diMeo-phenyl 976 —CH₂— pyridin-2,4-diyl —O— 3,5-diMeO-phenyl 977 —CH₂— pyridin-2,4-diyl —O— cyclopropyl 978 —CH₂— pyridin-2,4-diyl —O— cyclobutyl 979 —CH₂— pyridin-2,4-diyl —O— cyclopentyl 980 —CH₂— pyridin-2,4-diyl —O— cyclohexyl 981 —CH₂— pyridin-2,4-diyl —O— 2-furanyl 982 —CH₂— pyridin-2,4-diyl —O— 2-thienyl 983 —CH₂— pyridin-2,4-diyl CH₂CH₂ 2-imidazolyl 984 —CH₂— pyridin-2,4-diyl —O— 2-pyridyl 985 —CH₂— pyridin-2,4-diyl —O— 3-pyridyl 986 —CH₂— pyridin-2,4-diyl —O— 4-pyridyl 987 —CH₂— pyridin-2,4-diyl CH₂CH₂ N-morpholinyl 988 —CH₂— pyridin-2,4-diyl CH₂CH₂ N-piperidinyl 989 —CH₂— pyridin-2,4-diyl —O— 3-Me-2-pyridyl 990 —CH₂— pyridin-2,4-diyl —O— 4-Me-2-pyridyl 991 —CH₂— pyridin-2,4-diyl CH₂CH₂ 1-indolyl 992 —CH₂— pyridin-2,4-diyl —O— 2-benzothienyl 993 —CH₂— pyridin-2,4-diyl —O— 2-benzofuranyl 994 —CH₂— pyridin-2,4-diyl CH₂CH₂ 1-benzimidazole 995 —CH₂— pyridin-2,4-diyl —O— 2-naphthyl 996 —CH₂— pyridin-4,2-diyl —O— phenyl 997 —CH₂— pyridin-4,2-diyl —O— 3,3- diphenylmethyl 998 —CH₂— pyridin-4,2-diyl —O— 2-F-phenyl 999 —CH₂— pyridin-4,2-diyl —O— 3-F-phenyl 1000 —CH₂— pyridin-4,2-diyl —O— 4-F-phenyl 1001 —CH₂— pyridin-4,2-diyl —O— 2-Cl-phenyl 1002 —CH₂— pyridin-4,2-diyl —O— 3-Cl-phenyl 1003 —CH₂— pyridin-4,2-diyl —O— 4-Cl-phenyl 1004 —CH₂— pyridin-4,2-diyl —O— 2-Me-phenyl 1005 —CH₂— pyridin-4,2-diyl —O— 3-Me-phenyl 1006 —CH₂— pyridin-4,2-diyl —O— 4-Me-phenyl 1007 —CH₂— pyridin-4,2-diyl —O— 2-MeO-phenyl 1008 —CH₂— pyridin-4,2-diyl —O— 3-MeO-phenyl 1009 —CH₂— pyridin-4,2-diyl —O— 4-MeO-phenyl 1010 —CH₂— pyridin-4,2-diyl —O— 2-MeS-phenyl 1011 —CH₂— pyridin-4,2-diyl —O— 3-MeS-phenyl 1012 —CH₂— pyridin-4,2-diyl —O— 4-MeS-phenyl 1013 —CH₂— pyridin-4,2-diyl —O— 2-F₃C-phenyl 1014 —CH₂— pyridin-4,2-diyl —O— 3-F₃C-phenyl 1015 —CH₂— pyridin-4,2-diyl —O— 4-F₃C-phenyl 1016 —CH₂— pyridin-4,2-diyl —O— 2,3-diF-phenyl 1017 —CH₂— pyridin-4,2-diyl —O— 2,4-diF-phenyl 1018 —CH₂— pyridin-4,2-diyl —O— 2,5-diF-phenyl 1019 —CH₂— pyridin-4,2-diyl —O— 2,6-diF-phenyl 1020 —CH₂— pyridin-4,2-diyl —O— 3,4-diF-phenyl 1021 —CH₂— pyridin-4,2-diyl —O— 3,5-diF-phenyl 1022 —CH₂— pyridin-4,2-diyl —O— 2,3-diCl-phenyl 1023 —CH₂— pyridin-4,2-diyl —O— 2,4-diCl-phenyl 1024 —CH₂— pyridin-4,2-diyl —O— 2,5-diCl-phenyl 1025 —CH₂— pyridin-4,2-diyl —O— 2,6-diCl-phenyl 1026 —CH₂— pyridin-4,2-diyl —O— 3,4-diCl-phenyl 1027 —CH₂— pyridin-4,2-diyl —O— 3,5-diCl-phenyl 1028 —CH₂— pyridin-4,2-diyl —O— 2-Cl-3-F-phenyl 1029 —CH₂— pyrldin-4,2-diyl —O— 2-Cl-4-F-phenyl 1030 —CH₂— pyridin-4,2-diyl —O— 2-Cl-5-F-phenyl 1031 —CH₂— pyridin-4,2-diyl —O— 3-Cl-4-F-phenyl 1032 —CH₂— pyridin-4,2-diyl —O— 3-Cl-5-F-phenyl 1033 —CH₂— pyridin-4,2-diyl —O— 4-Cl-2-F-phenyl 1034 —CH₂— pyridin-4,2-diyl —O— 4-Cl-3-F-phenyl 1035 —CH₂— pyridin-4,2-diyl —O— 2,3-diMeO-phenyl 1036 —CH₂— pyridin-4,2-diyl —O— 2,4-diMeO-phenyl 1037 —CH₂— pyridin-4,2-diyl —O— 2,5-diMeO-phenyl 1038 —CH₂— pyridin-4,2-diyl —O— 2,6-diMeO-phenyl 1039 —CH₂— pyridin-4,2-diyl —O— 3,4-diMeO-phenyl 1040 —CH₂— pyridin-4,2-diyl —O— 3,5-diMeO-phenyl 1041 —CH₂— pyridin-4,2-diyl —O— cyclopropyl 1042 —CH₂— pyridin-4,2-diyl —O— cyclobutyl 1043 —CH₂— pyridin-4,2-diyl —O— cyclopentyl 1044 —CH₂— pyridin-4,2-diyl —O— cyclohexyl 1045 —CH₂— pyridin-4,2-diyl —O— 2-furanyl 1046 —CH₂— pyridin-4,2-diyl —O— 2-thienyl 1047 —CH₂— pyridin-4,2-diyl CH₂CH₂ 2-imidazolyl 1048 —CH₂— pyridin-4,2-diyl —O— 2-pyridyl 1049 —CH₂— pyridin-4,2-diyl —O— 3-pyridyl 1050 —CH₂— pyridin-4,2-diyl —O— 4-pyridyl 1051 —CH₂— pyridin-4,2-diyl CH₂CH₂ N-morpholinyl 1052 —CH₂— pyridin-4,2-diyl CH₂CH₂ N-piperidinyl 1053 —CH₂— pyridin-4,2-diyl —O— 3-Me-2-pyridyl 1054 —CH₂— pyridin-4,2-diyl —O— 4-Me-2-pyridyl 1055 —CH₂— pyridin-4,2-diyl CH₂CH₂ 1-indolyl 1056 —CH₂— pyridin-4,2-diyl —O— 2-benzothienyl 1057 —CH₂— pyridin-4,2-diyl —O— 2-benzofuranyl 1058 —CH₂— pyridin-4,2-diyl CH₂CH₂ 1-benzimidazole 1059 —CH₂— pyridin-4,2-diyl —O— 2-naphthyl 1060 —CH₂— piperidin-1,3- —O— phenyl diyl 1061 —CH₂— piperidin-1,3- —O— diyl 1062 —CH₂— piperidin-1,3 —O— 2-F-phenyl diyl 1063 —CH₂— piperidin-1,3- —O— 3-F-phenyl diyl 1064 —CH₂— piperidin-1,3- —O— 4-F-phenyl diyl 1065 —CH₂— piperidin-1,3- —O— 2-Cl-phenyl diyl 1066 —CH₂— piperidin-1,3- —O— 3-Cl-phenyl diyl 1067 —CH₂— piperidin-1,3- —O— 4-Cl-phenyl diyl 1068 —CH₂— piperidin-1,3- —O— 2-Me-phenyl diyl 1069 —CH₂— piperidin-1,3- —O— 3-Me-phenyl diyl 1070 —CH₂— piperidin-1,3- —O— 4-Me-phenyl diyl 1071 —CH₂— piperidin-1,3- —O— 2-MeO-phenyl diyl 1072 —CH₂— piperidin-1,3- —O— 3-MeO-phenyl diyl 1073 —CH₂— piperidin-1,3- —O— 4-MeO-phenyl diyl 1074 —CH₂— piperidin-1,3- —O— 2-MeS-phenyl diyl 1075 —CH₂— piperidin-1,3- —O— 3-MeS-phenyl diyl 1076 —CH₂— piperidin-1,3- —O— 4-MeS-phenyl diyl 1077 —CH₂— piperidin-1,3- —O— 2-F₃C-phenyl diyl 1078 —CH₂— piperidin-1,3- —O— 3-F₃C-phenyl diyl 1079 —CH₂— piperidin-1,3- —O— 4-F₃C-phenyl diyl 1080 —CH₂— piperidin-1,3- —O— 2,3-diF-phenyl diyl 1081 —CH₂— piperidin-1,3- —O— 2,4-diF-phenyl diyl 1082 —CH₂— piperidin-1,3- —O— 2,5-diF-phenyl diyl 1083 —CH₂— piperidin-1,3- —O— 2,6-diF-phenyl diyl 1084 —CH₂— piperidin-1,3- —O— 3,4-diF-phenyl diyl 1085 —CH₂— piperidin-1,3- —O— 3,5-diF-phenyl diyl 1086 —CH₂— piperidin-1,3- —O— 2,3-diCl-phenyl diyl 1087 —CH₂— piperidin-1,3- —O— 2,4-diCl-phenyl diyl 1088 —CH₂— piperidin-1,3- —O— 2,5-diCl-phenyl diyl 1089 —CH₂— piperidin-1,3- —O— 2,6-diCl-phenyl diyl 1090 —CH₂— piperidin-1,3- —O— 3,4-diCl-phenyl diyl 1091 —CH₂— piperidin-1,3- —O— 3,5-diCl-phenyl diyl 1092 —CH₂— piperidin-1,3- —O— 2-Cl-3-F-phenyl diyl 1093 —CH₂— piperidin-1,3- —O— 2-Cl-4-F-phenyl diyl 1094 —CH₂— piperidin-1,3- —O— 2-Cl-5-F-phenyl diyl 1095 —CH₂— piperidin-1,3- —O— 3-Cl-4-F-phenyl diyl 1096 —CH₂— piperidin-1,3- —O— 3-Cl-5-F-phenyl diyl 1097 —CH₂— piperidin-1,3- —O— 4-Cl-2-F-phenyl diyl 1098 —CH₂— piperidin-1,3- —O— 4-Cl-3-F-phenyl diyl 1099 —CH₂— piperidin-1,3- —O— 2,3-diMeo-phenyl diyl 1100 —CH₂— piperidin-1,3- —O— 2,4-diMeo-phenyl diyl 1101 —CH₂— piperidin-1,3- —O— 2,5-diMeo-phenyl diyl 1102 —CH₂— piperidin-1,3- —O— 2,6-diMeo-phenyl diyl 1103 —CH₂— piperidin-1,3- —O— 3,4-diMeo-phenyl diyl 1104 —CH₂— piperidin-1,3- —O— 3,5-diMeO-phenyl diyl 1105 —CH₂— piperidin-1,3- —O— Cyclopropyl diyl 1106 CH2- piperidin-1,3- —O— Cyclobutyl diyl 1107 —CH₂— piperidin-1,3- —O— Cyclopentyl diyl 1108 -Ca2- piperidin-1,3- —O— Cyclohexyl diyl 1109 —CH₂— piperidin-1,3- —O— 2-furanyl diyl 1110 —CH₂— piperidin-1,3- —O— 2-thienyl diyl 1111 —CH₂— piperidin-1,3- CH₂CH₂ 2-imidazolyl diyl 1112 —CH₂— piperidin-1,3- —O— 2-pyridyl diyl 1113 —CH₂— piperidin-1,3- —O— 3-pyridyl diyl 1114 —CH₂— piperidin-1,3- —O— 4-pyridyl diyl 1115 —CH₂— piperidin-1,3- CH₂CH₂ N-morpholinyl diyl 1116 —CH₂— piperidin-1,3- CH₂CH₂ N-piperidinyl diyl 1117 —CH₂— piperidin-1,3- —O—3-Me-2-pyridyl diyl 1118 —CH₂— piperidin-1,3- —O— 4-Me-2-pyridyl diyl 1119 —CH₂— piperidin-1,3- CH₂CH₂ 1-indolyl diyl 1120 —CH₂— piperidin-1,3- —O— 2-benzothienyl diyl 1121 —CH₂— piperidin-1,3- —O— 2-berizofuranyl diyl 1122 —CH₂— piperidin-1,3- CH₂CH₂ 1-benzimidazole diyl 1123 —CH₂— piperidin-1,3- —O— 2-naphthyl diyl 1124 —CH₂— piperidin-3,1- —O— phenyl diyl 1125 —CH₂— piperidin-3,1- —O— 3,3- diyl diphenylmethyl 1126 —CH₂— piperidin-3,1- —O— 2-F-phenyl diyl 1127 —CH₂— piperidin-3,1- —O— 3-F-phenyl diyl 1128 —CH₂— piperidin-3,1- —O— 4-F-phenyl diyl 1129 —CH₂— piperidin-3,1- —O— 2-Cl-phenyl diyl 1130 —CH₂— piperidin-3,1- —O— 3-Cl-phenyl diyl 1131 —CH₂— piperidin-3,1- —O— 4-Cl-phenyl diyl 1132 —CH₂— piperidin-3,1- —O— 2-Me-phenyl diyl 1133 —CH₂— piperidin-3,1- —O— 3-Me-phenyl diyl 1134 —CH₂— piperidin-3,1- —O— 4-Me-phenyl diyl 1135 —CH₂— piperidin-3,1- —O— 2-MeO-phenyl diyl 1136 —CH₂— piperidin-3,1- —O— 3-MeO-phenyl diyl 1137 —CH₂— piperidin-3,1- —O— 4-MeO-phenyl diyl 1138 —CH₂— piperidin-3,1- —O— 2-MeS-phenyl diyl 1139 —CH₂— piperidin-3,1- —O— 3-MeS-phenyl diyl 1140 —CH₂— piperidin-3,1- —O— 4-MeS-phenyl diyl 1141 —CH₂— piperidin-3,1- —O— 2-F₃C-phenyl diyl 1142 —CH₂— piperidin-3,1- —O— 3-F₃C-phenyl diyl 1143 —CH₂— piperidin-3,1- —O— 4-F₃C-phenyl diyl 1144 —CH₂— piperidin-3,1- —O— 2,3-diF-phenyl diyl 1145 —CH₂— piperidin-3,1- —O— 2,4-diF-phenyl diyl 1146 —CH₂— piperidin-3,1- —O— 2,5-diF-phenyl diyl 1147 —CH₂— piperidin-3,1- —O— 2,6-diF-phenyl diyl 1148 —CH₂— piperidin-3,1- —O— 3,4-diF-phenyl diyl 1149 —CH₂— piperidin-3,1- —O— 3,5-diF-phenyl diyl 1150 —CH₂— piperidin-3,1- —O— 2,3-diCl-phenyl diyl 1151 —CH₂— piperidin-3,1- —O— 2,4-diCl-phenyl diyl 1152 —CH₂— piperidin-3,1- —O— 2,5-diCl-phenyl diyl 1153 —CH₂— piperidin-3,1- —O— 2,6-diCl-phenyl diyl 1154 —CH₂— piperidin-3,1- —O— 3,4-diCl-phenyl diyl 1155 —CH₂— piperidin-3,1- —O— 3,5-diCl-phenyl diyl 1156 —CH₂— piperidin-3,1- —O— 2-Cl-3-F-phenyl diyl 1157 —CH₂— piperidin-3,1- —O— 2-Cl-4-F-phenyl diyl 1158 —CH₂— piperidin-3,1- —O— 2-Cl-5-F-phenyl diyl 1159 —CH₂— piperidin-3,1- —O— 3-Cl-4-F-phenyl diyl 1160 —CH₂— piperidin-3,1- —O— 3-Cl-5-F-phenyl diyl 1161 —CH₂— piperidin-3,1- —O— 4-Cl-2-F-phenyl diyl 1162 —CH₂— piperidin-3,1- —O— 4-Cl-3-F-phenyl diyl 1163 —CH₂— piperidin-3,1- —O— 2,3-diMeO-phenyl diyl 1164 —CH₂— piperidin-3,1- —O— 2,4-diMeO-phenyl diyl 1165 —CH₂— piperidin-3,1- —O— 2,5-diMeO-phenyl diyl 1166 —CH₂— piperidin-3,1- —O— 2,6-diMeO-phenyl diyl 1167 —CH₂— piperidin-3,1- —O— 3 4-diMeO-phenyl diyl 1168 —CH₂— piperidin-3,1- —O— 3,5-diMeo-phenyl diyl 1169 —CH₂— piperidin-3,1- —O— Cyclopropyl diyl 1170 —CH₂— piperidin-3,1- —O— Cyclobutyl diyl 1171 —CH₂— piperidin-3,1- —O— Cyclopentyl diyl 1172 —CH₂— piperidin-3,1- —O— Cyclohexyl diyl 1173 —CH₂— piperidin-3,1- —O— 2-furanyl diyl 1174 —CH₂— piperidin-3,1- —O— 2-thienyl diyl 1175 —CH₂— piperidin-3,1- CH₂CH₂ 2-imidazolyl diyl 1176 —CH₂— piperidin-3,1- —O— 2-pyridyl diyl 1177 —CH₂— piperidin-3,1- —O— 3-pyridyl diyl 1178 —CH₂— piperidin-3,1- —O— 4-pyridyl diyl 1179 —CH₂— piperidin-3,1- CH₂CH₂ N-morpholinyl diyl 1180 —CH₂— piperidin-3,1- CH₂CH₂ N-piperidinyl diyl 1181 —CH₂— piperidin-3,1- —O— 3-Me-2-pyridyl diyl 1182 —CH₂— piperidin-3,1- —O— 4-Me-2-pyridyl diyl 1183 —CH₂— piperidin-3,1- CH₂CH₂ 1-indolyl diyl 1184 —CH₂— piperidin-3,1- —O— 2-benzothienyl diyl 1185 —CH₂— piperidin-3,1- —O— 2-benzofuranyl diyl 1186 —CH₂— piperidin-3,1- CH₂CH₂ 1-benzimidazole diyl 1187 —CH₂— piperidin-3,1- —O— 2-naphthyl diyl 1188 —CH₂— cyclohex-1,3-diyl —O— phenyl 1189 —CH₂— cyclohex-1,3-diyl —O— 3,3- diphenylmethyl 1190 —CH₂— cyclohex-1,3-diyl —O— 2-F-phenyl 1191 —CH₂— cyclohex-1,3-diyl —O— 3-F-phenyl 1192 —CH₂— cyclohex-1,3-diyl —O— 4-F-phenyl 1193 —CH₂— cyclohex-1,3-diyl —O— 2-Cl-phenyl 1194 —CH₂— cyclohex-1,3-diyl —O— 3-Cl-phenyl 1195 —CH₂— cyclohex-1,3-diyl —O— 4-Cl-phenyl 1196 —CH₂— cyclohex-1,3-diyl —O— 2-Me-phenyl 1197 —CH₂— cyclohex-1,3-diyl —O— 3-Me-phenyl 1198 —CH₂— cyclohex-1,3-diyl —O— 4-Me-phenyl 1199 —CH₂— cyclohex-1,3-diyl —O— 2-MeO-phenyl 1200 —CH₂— cyclohex-1,3-diyl —O— 3-MeO-phenyl 1201 —CH₂— cyclohex-1,3-diyl —O— 4-MeO-phenyl 1202 —CH₂— cyclohex-1,3-diyl —O— 2-MeS-phenyl 1203 —CH₂— cyclohex-1,3-diyl —O— 3-MeS-phenyl 1204 —CH₂— cyclohex-1,3-diyl —O— 4-MeS-phenyl 1205 —CH₂— cyclohex-1,3-diyl —O— 2-F₃C-phenyl 1206 —CH₂— cyclohex-1,3-diyl —O— 3-F₃C-phenyl 1207 —CH₂— cyclohex-1,3-diyl —O— 4-F₃C-phenyl 1208 —CH₂— cyclohex-1,3-diyl —O— 2,3-diF-phenyl 1209 —CH₂— cyclohex-1,3-diyl —O— 2,4-diF-phenyl 1210 —CH₂— cyclohex-1,3-diyl —O— 2,5-diF-phenyl 1211 —CH₂— cyclohex-1,3-diyl —O— 2,6-diF-phenyl 1212 —CH₂— cyclohex-1,3-diyl —O— 3,4-diF-phenyl 1213 —CH₂— cyclohex-1,3-diyl —O— 3,5-diF-phenyl 1214 —CH₂— cyclohex-1,3-diyl —O— 2,3-diCl-phenyl 1215 —CH₂— cyclohex-1,3-diyl —O— 2,4-diCl-phenyl 1216 —CH₂— cyclohex-1,3-diyl —O— 2,5-diCl-phenyl 1217 —CH₂— cyclohex-1,3-diyl —O— 2,6-diCl-phenyl 1218 —CH₂— cyclohex-1,3-diyl —O— 3,4-diCl-phenyl 1219 —CH₂— cyclohex-1,3-diyl —O— 3,5-diCl-phenyl 1220 —CH₂— cyclohex-1,3-diyl —O— 2-Cl-3-F-phenyl 1221 —CH₂— cyclohex-1,3-diyl —O— 2-Cl-4-F-phenyl 1222 —CH₂— cyclohex-1,3-diyl —O— 2-Cl-5-F-phenyl 1223 —CH₂— cyclohex-1,3-diyl —O— 3-Cl-4-F-phenyl 1224 —CH₂— cyclohex-1,3-diyl —O— 3-Cl-5-F-phenyl 1225 —CH₂— cyclohex-1,3-diyl —O— 4-Cl-2-F-phenyl 1226 —CH₂— cyclohex-1,3-diyl —O— 4-Cl-3-F-phenyl 1227 —CH₂— cyclohex-1,3-diyl —O— 2,3-diMeo-phenyl 1228 —CH₂— cyclohex-1,3-diyl —O— 2,4-diMeo-phenyl 1229 —CH₂— cyclohex-1,3-diyl —O— 2,5-diMeO-phenyl 1230 —CH₂— cyclohex-1,3-diyl —O— 2,6-diMeo-phenyl 1231 —CH₂— cyclohex-1,3-diyl —O— 3,4-diMeO-phenyl 1232 —CH₂— cyclohex-1,3-diyl —O— 3,5-diMeO-phenyl 1233 —CH₂— cyclohex-1,3-diyl —O— Cyclopropyl 1234 —CH₂— cyclohex-1,3-diyl —O— Cyclobutyl 1235 —CH₂— cyclohex-1,3-diyl —O— Cyclopentyl 1236 —CH₂— cyclohex-1,3-diyl —O— Cyclohexyl 1237 —CH₂— cyclohex-1,3-diyl —O— 2-furanyl 1238 —CH₂— cyclohex-1,3-diyl —O— 2-thienyl 1239 —CH₂— cyclohex-1,3-diyl CH₂CH₂ 2-imidazolyl 1240 —CH₂— cyclohex-1,3-diyl —O— 2-pyridyl 1241 —CH₂— cyclohex-1,3-diyl —O— 3-pyridyl 1242 —CH₂— cyclohex-1,3-diyl —O— 4-pyridyl 1243 —CH₂— cyclohex-1,3-diyl CH₂CH₂ N-morpholinyl 1244 —CH₂— cyclohex-1,3-diyl CH₂CH₂ N-piperidinyl 1245 —CH₂— cyclohex-1,3-diyl —O— 3-Me-2-pyridyl 1246 —CH₂— cyclohex-1,3-diyl —O— 4-Me-2-pyridyl 1247 —CH₂— cyclohex-1,3-diyl CH₂CH₂ 1-indoly2 1248 —CH₂— cyclohex-1,3-diyl —O— 2-benzothienyl 1249 —CH₂— cyclohex-1,3-diyl —O— 2-benzofuranyl 1250 —CH₂— cyclohex-1,3-diyl CH₂CH₂ i-benzimidazole 1251 —CH₂— cyclohex-1,3-diyl —O— 2-naphthyl 1252 —CH₂— cyclopropan-1,2- —O— phenyl diyl 1253 —CH₂— cyclopropan-1,2- —O— 3,3- diyl diphenylmethyl 1254 —CH₂— cyclopropan-1,2- —O— 2-F-phenyl diyl 1255 —CH₂— cyclopropan-1,2- —O— 3-F-phenyl diyl 1256 —CH₂— cyclopropan-1,2- —O— 4-F-phenyl diyl 1257 —CH₂— cyclopropan-1,2- —O— 2-Cl-phenyl diyl 1258 —CH₂— cyclopropan-1,2- —O— 3-Cl-phenyl diyl 1259 —CH₂— cyclopropan-1,2- —O— 4-Cl-phenyl diyl 1260 —CH₂— cyclopropan-1,2- —O— 2-Me-phenyl diyl 1261 —CH₂— cyclopropan-1,2- —O— 3-Me-phenyl diyl 1262 —CH₂— cyclopropan-1,2- —O— 4-Me-phenyl diyl 1263 —CH₂— cyclopropan-1,2- —O— 2-MeO-phenyl diyl 1264 —CH₂— cyclopropan-1,2- —O— 3-MeO-phenyl diyl 1265 —CH₂— cyclopropan-1,2- —O— 4-MeO-phenyl diyl 1266 —CH₂— cyclopropan-1,2- —O— 2-MeS-phenyl diyl 1267 —CH₂— cyclopropan-1,2- —O— 3-MeS-phenyl diyl 1268 —CH₂— cyclopropan-1,2- —O— 4-MeS-phenyl diyl 1269 —CH₂— cyclopropan-1,2- —O— 2-F₃C-phenyl diyl 1270 —CH₂— cyclopropan-1,2- —O— 3-F₃C-phenyl diyl 1271 —CH₂— cyclopropan-1,2- —O— 4-F₃C-phenyl diyl 1272 —CH₂— cyclopropan-1,2- —O— 2,3-diF-phenyl diyl 1273 —CH₂— cyclopropan-1,2- —O— 2,4-diF-phenyl diyl 1274 —CH₂— cyclopropan-1,2- —O— 2,5-diF-phenyl diyl 1275 —CH₂— cyclopropan-1,2- —O— 2,6-diF-phenyl diyl 1276 —CH₂— cyclopropan-1,2- —O— 3,4-diF-phenyl diyl 1277 —CH₂— cyclopropan-1,2- —O— 3,5-diF diyl 1278 —CH₂— cyclopropan-1,2- —O— 2,3-diCl-phenyl diyl 1279 —CH₂— cyclopropan-1,2- —O— 2,4-diCl-phenyl diyl 1280 —CH₂— cyclopropan-1,2- —O— 2,5-diCl-phenyl diyl 1281 —CH₂— cyclopropan-1,2- —O— 2,6-diCl-phenyl diyl 1282 —CH₂— cyclopropan-1,2- —O— 3,4-diCl-phenyl diyl 1283 —CH₂— cyclopropan-1,2- —O— 3,5-diCl-phenyl diyl 1284 —CH₂— cyclopropan-1,2- —O— 2-Cl-3-F-phenyl diyl 1285 —CH₂— cyclopropan-1,2- —O— 2-Cl-4-F-phenyl diyl 1286 —CH₂— cyclopropan-1,2- —O— 2-Cl-5-F-phenyl diyl 1287 —CH₂— cyclopropan-1,2- —O— 3-Cl-4-F-phenyl diyl 1288 —CH₂— cyclopropan-1,2- —O— 3-Cl-5-F-phenyl diyl 1289 —CH₂— cyclopropan-1,2- —O— 4-Cl-2-F-phenyl diyl 1290 —CH₂— cyclopropan-1,2- —O— 4-Cl-3-F-phenyl diyl 1291 —CH₂— cyclopropan-1,2- —O— 2,3-diMeo-phenyl diyl 1292 —CH₂— cyclopropan-1,2- —O— 2,4-diMeo-phenyl diyl 1293 —CH₂— cyclopropan-1,2- —O— 2,5-diMeo-phenyl diyl 1294 —CH₂— cyclopropan-1,2- —O— 2,6-diMeo-phenyl diyl 1295 —CH₂— cyclopropan-1,2- —O— 3,4-diMeo-phenyl diyl 1296 —CH₂— cyclopropan-1,2- —O— 3,5-diMeo-phenyl diyl 1297 —CH₂— cyclopropan-1,2- —O— Cyclopropyl diyl 1298 —CH₂— cyclopropan-1,2- —O— Cyclobutyl diyl 1299 —CH₂— cyclopropan-1,2- —O— Cyclopentyl diyl 1300 —CH₂— cyclopropan-1,2- —O— Cyclohexyl diyl 1301 —CH₂— cyclopropan-1,2- —O— 2-furanyl diyl 1302 —CH₂— cyclopropan-1,2- —O— 2-thienyl diyl 1303 —CH₂— cyclopropan-1,2- CH₂CH₂ 2-imidazolyl diyl 1304 —CH₂— cyclopropan-1,2- —O— 2-pyridyl diyl 1305 —CH₂— cyclopropan-1,2- —O— 3-pyridyl diyl 1306 —CH₂— cyclopropan-1,2- —O— 4-pyridyl diyl 1307 —CH₂— cyclopropan-1,2- CH₂CH₂ N-morpholinyl diyl 1308 —CH₂— cyclopropan-1,2- CH₂CH₂ N-piperidinyl diyl 1309 —CH₂— cyclopropan-1,2- —O— 3-Me-2-pyridyl diyl 1310 —CH₂— cyclopropan-1,2- —O— 4-Me-2-pyridyl diyl 1311 —CH₂— cyclopropan-1,2- CH₂CH₂ 1-indolyl diyl 1312 —CH₂— cyclopropan-1,2- —O— 2-benzothienyl diyl 1313 —CH₂— cyclopropan-1,2- —O— 2-benzofuranyl diyl 1314 —CH₂— cyclopropan-1,2- CH₂CH₂ 1-benzimidazole diyl 1315 —CH₂— cyclopropan-1,2- —O— 2-naphthyl diyl 1316 —CH₂— cyclopentan-1,3- —O— phenyl diyl 1317 —CH₂— cyclopentan-1,3- —O— 3,3- diyl 1318 —CH₂— cyclopentan-1,3- —O— 2-F-phenyl diyl 1319 —CH₂— cyclopentan-1,3- —O— 3-F-phenyl diyl 1320 —CH₂— cyclopentan-1,3- —O— 4-F-phenyl diyl 1321 —CH₂— cyclopentan-1,3- —O— 2-Cl-phenyl diyl 1322 —CH₂— cyclopentan-1,3- —O— 3-Cl-phenyl diyl 1323 —CH₂— cyclopentan-1,3- —O— 4-Cl-phenyl diyl 1324 —CH₂— cyclopentan-1,3- —O— 2-Me-phenyl diyl 1325 —CH₂— cyclopentan-1,3- —O— 3-Me-phenyl diyl 1326 —CH₂— cyclopentan-1,3- —O— 4-Me-phenyl diyl 1327 —CH₂— cyclopentan-1,3- —O— 2-MeO-phenyl diyl 1328 —CH₂— cyclopentan-1,3- —O— 3-MeO-phenyl diyl 1329 —CH₂— cyclopentan-1,3- —O— 4-MeO-phenyl diyl 1330 —CH₂— cyclopentan-1,3- —O— 2-MeS-phenyl diyl 1331 —CH₂— cyclopentan-1,3- —O— 3-MeS-phenyl diyl 1332 —CH₂— cyclopentan-1,3- —O— 4-MeS-phenyl diyl 1333 —CH₂— cyclopentan-1,3- —O— 2-F₃C-phenyl diyl 1334 —CH₂— cyclopentan-1,3- —O— 3-F₃C-phenyl diyl 1335 —CH₂— cyclopentan-1,3- —O— 4-F₃C-phenyl diyl 1336 —CH₂— cyclopentan-1,3- —O— 2,3-diF-phenyl diyl 1337 —CH₂— cyclopentan-1,3- —O— 2,4-diF-phenyl diyl 1338 —CH₂— cyclopentan-1,3- —O— 2,5-diF-phenyl diyl 1339 —CH₂— cyclopentan-1,3- —O— 2,6-diF-phenyl diyl 1340 —CH₂— cyclopentan-1,3- —O— 3,4-diF-phenyl diyl 1341 —CH₂— cyclopentan-1,3- —O— 3,5-diF-phenyl diyl 1342 —CH₂— cyclopentan-1,3- —O— 2,3-diCl-phenyl diyl 1343 —CH₂— cyclopentan-1,3- —O— 2,4-diCl-phenyl diyl 1344 —CH₂— cyclopentan-1,3- —O— 2,5-diCl-phenyl diyl 1345 —CH₂— cyclopentan-1,3- —O— 2,6-diCl-phenyl diyl 1346 —CH₂— cyclopentan-1,3- —O— 3,4-diCl-phenyl diyl 1347 —CH₂— cyclopentan-1,3- —O— 3,5-diCl-phenyl diyl 1348 —CH₂— cyclopentan-1,3- —O— 2-Cl-3-F-phenyl diyl 1349 —CH₂— cyclopentan-1,3- —O— 2-Cl-4-F-phenyl diyl 1350 —CH₂— cyclopentan-1,3- —O— 2-Cl-5-F-phenyl diyl 1351 —CH₂— cyclopentan-1,3- —O— 3-Cl-4-F-phenyl diyl 1352 —CH₂— cyclopentan-1,3- —O— 3-Cl-5-F-phenyl diyl 1353 —CH₂— cyclopentan-1,3- —O— 4-Cl-2-F-phenyl diyl 1354 —CH₂— cyclopentan-1,3- —O— 4-Cl-3-F-phenyl diyl 1355 —CH₂— cyclopentan-1,3- —O— 2,3-diMeo-phenyl diyl 1356 —CH₂— cyclopentan-1,3- —O— 2,4-diMeo-phenyl diyl 1357 —CH₂— cyclopentan-1,3- —O— 2,5-diMeO-phenyl diyl 1358 —CH₂— cyclopentan-1,3- —O— 2,6-diMeO-phenyl diyl 1359 —CH₂— cyclopentan-1,3- —O— 3,4-diMeO-phenyl diyl 1360 —CH₂— cyclopentan-1,3- —O— 3,5-diMeO-phenyl diyl 1361 —CH₂— cyclopentan-1,3- —O— Cyclopropyl diyl 1362 —CH₂— cyclopentan-1,3- —O— Cyclobutyl diyl 1363 —CH₂— cyclopentan-1,3- —O— Cyclopentyl diyl 1364 —CH₂— cyclopentan-1,3- —O— Cyclohexyl diyl 1365 —CH₂— cyclopentan-1,3- —O— 2-furanyl diyl 1366 —CH₂— cyclopentan-1,3- —O— 2-thienyl diyl 1367 —CH₂— cyclopentan-1,3- CH₂CH₂ 2-imidazolyl diyl 1368 —CH₂— cyclopentan-1,3- —O— 2-pyridyl diyl 1369 —CH₂— cyclopentan-1,3- —O— 3-pyridyl diyl 1370 —CH₂— cyclopentan-1,3- —O— 4-pyridyl diyl 1371 —CH₂— cyclopentan-1,3- CH₂CH₂ N-morpholinyl diyl 1372 —CH₂— cyclopentan-1,3- CH₂CH₂ N-piperidinyl diyl 1373 —CH₂— cyclopentan-1,3- —O— 3-Me-2-pyridyl diyl 1374 —CH₂— cyclopentan13 —O— 4-Me-2-pyridyl diyl 1375 —CH₂— cyclopentan-1,3- CH₂CH₂ 1-indolyl diyl 1376 —CH₂— cyclopentan-1,3- —O— 2-benzothienyl diyl 1377 —CH₂— cyclopentan-1,3- —O— 2-benzofuranyl diyl 1378 —CH₂— cyclopentan-1,3- CH₂CH₂ 1-benzimidazole diyl 1379 —CH₂— cyclopentan-1,3- —O— 2-naphthyl diyl 1380 —CH₂— bond bond phenyl 1381 —CH₂— bond bond 3,3-diphenyl 1382 —CH₂— bond bond 2-F-phenyl 1383 —CH₂— bond bond 3-F-phenyl 1384 —CH₂— bond bond 4-F-phenyl 1385 —CH₂— bond bond 2-Cl-phenyl 1386 —CH₂— bond bond 3-Cl-phenyl 1387 —CH₂— bond bond 4-Cl-phenyl 1388 —CH₂— bond bond 2-Me-phenyl 1389 —CH₂— bond bond 3-Me-phenyl 1390 —CH₂— bond bond 4-Me-phenyl 1391 —CH₂— bond bond 2-MeO-phenyl 1392 —CH₂— bond bond 3-MeO-phenyl 1393 —CH₂— bond bond 4-MeO-phenyl 1394 —CH₂— bond bond 2-MeS-phenyl 1395 —CH₂— bond bond 3-MeS-phenyl 1396 —CH₂— bond bond 4-MeS-phenyl 1397 —CH₂— bond bond 2-F₃C-phenyl 1398 —CH₂— bond bond 3-F₃C-phenyl 1399 —CH₂— bond bond 4-F₃C-phenyl 1400 —CH₂— bond bond 2,3-diF-phenyl 1401 —CH₂— bond bond 2,4-diF-phenyl 1402 —CH₂— bond bond 2,5-diF-phenyl 1403 —CH₂— bond bond 2,6-diF-phenyl 1404 —CH₂— bond bond 3,4-diF-phenyl 1405 —CH₂— bond bond 3,5-diF-phenyl 1406 —CH₂— bond bond 2,3-diCl-phenyl 1407 —CH₂— bond bond 2,4-diCl-phenyl 1408 —CH₂— bond bond 2,5-diCl-phenyl 1409 —CH₂— bond bond 2,6-diCl-phenyl 1410 —CH₂— bond bond 3,4-diCl-phenyl 1411 —CH₂— bond bond 3,5-diCl-phenyl 1412 —CH₂— bond bond 2-Cl-3-F-phenyl 1413 —CH₂— bond bond 2-Cl-4-F-phenyl 1414 —CH₂— bond bond 2-Cl-5-F-phenyl 1415 —CH₂— bond bond 3-Cl-4-F-phenyl 1416 —CH₂— bond bond 3-Cl-5-F-phenyl 1417 —CH₂— bond bond 4-Cl-2-F-phenyl 1418 —CH₂— bond bond 4-Cl-3-F-phenyl 1419 —CH₂— bond bond 2,3-diMeO-phenyl 1420 —CH₂— bond bond 2,4-diMeO-phenyl 1421 —CH₂— bond bond 2,5-diMeO-phenyl 1422 —CH₂— bond bond 2,6-diMeO-phenyl 1423 —CH₂— bond bond 3,4-diMeO-phenyl 1424 —CH₂— bond bond 3,5-diMeO-phenyl 1425 —CH₂— bond bond cyclopropyl 1426 —CH₂— bond bond cyclobutyl 1427 —CH₂— bond bond cyclopentyl 1428 —CH₂— bond bond cyclohexyl 1429 —CH₂— bond bond 2-furany) 1430 —CH₂— bond bond 2-thienyl 1431 —CH₂— bond bond 2-imidazolyl 1432 —CH₂— bond bond 2-pyridyl 1433 —CH₂— bond bond 3-pyridyl 1434 —CH₂— bond bond 4-pyridyl 1435 —CH₂— bond bond N-morpholinyl 1436 —CH₂— bond bond N-piperidinyl 1437 —CH₂— bond bond 3-Me-2-pyridyl 1438 —CH₂— bond bond 4-Me-2-pyridyl 1439 —CH₂— bond bond 1-indolyl 1440 —CH₂— bond bond 2-benzothienyl 1441 —CH₂— bond bond 2-benzofuranyl 1442 —CH₂— bond bond 1-benzimidazole 1443 —CH₂— bond bond 2-naphthyl 1444 —CH₂CH₂— bond bond phenyl 1445 —CH₂CH₂— bond bond 3,3-diphenyl 1446 —CH₂CH₂— bond bond 2-F-phenyl 1447 —CH₂CH₂— bond bond 3-F-phenyl 1448 —CH₂CH₂— bond bond 4-F-phenyl 1449 —CH₂CH₂— bond bond 2-Cl-phenyl 1450 —CH₂CH₂— bond bond 3-Cl-phenyl 1451 —CH₂CH₂— bond bond 4-Cl-phenyl 1452 —CH₂CH₂— bond bond 2-Me-phenyl 1453 —CH₂CH₂— bond bond 3-Me-phenyl 1454 —CH₂CH₂— bond bond 4-Me-phenyl 1455 —CH₂CH₂— bond bond 2-MeO-phenyl 1456 —CH₂CH₂— bond bond 3-MeO-phenyl 1457 —CH₂CH₂— bond bond 4-MeO-phenyl 1458 —CH₂CH₂— bond bond 2-MeS-phenyl 1459 —CH₂CH₂— bond bond 3-MeS-phenyl 1460 —CH₂CH₂— bond bond 4-MeS-phenyl 1461 —CH₂CH₂— bond bond 2-F₃C-phenyl 1462 —CH₂CH₂— bond bond 3-F₃C-phenyl 1463 —CH₂CH₂— bond bond 4-F₃C-phenyl 1464 —CH₂CH₂— bond bond 2,3-diF-phenyl 1465 —CH₂CH₂— bond bond 2,4-diF-phenyl 1466 —CH₂CH₂— bond bond 2,5-diF-phenyl 1467 —CH₂CH₂— bond bond 2,6-diF-phenyl 1468 —CH₂CH₂— bond bond 3,4-diF-phenyl 1469 —CH₂CH₂— bond bond 3,5-diF-phenyl 1470 —CH₂CH₂— bond bond 2,3-diCl-phenyl 1471 —CH₂CH₂— bond bond 2,4-diCl-phenyl 1472 —CH₂CH₂— bond bond 2,5-diCl-phenyl 1473 —CH₂CH₂— bond bond 2,6-diCl-phenyl 1474 —CH₂CH₂— bond bond 3,4-diCl-phenyl 1475 —CH₂CH₂— bond bond 3,5-diCl-phenyl 1476 —CH₂CH₂— bond bond 2-Cl-3-F-phenyl 1477 —CH₂CH₂— bond bond 2-Cl-4-F-phenyl 1478 —CH₂CH₂— bond bond 2-Cl-5-F-phenyl 1479 —CH₂CH₂— bond bond 3-Cl-4-F-phenyl 1480 —CH₂CH₂— bond bond 3-Cl-5-F-phenyl 1481 —CH₂CH₂— bond bond 4-Cl-2-F-phenyl 1482 —CH₂CH₂— bond bond 4-Cl-3-F-phenyl 1483 —CH₂CH₂— bond bond 2,3-diMeO-phenyl 1484 —CH₂CH₂— bond bond 2,4-diMeO-phenyl 1485 —CH₂CH₂— bond bond 2,5-diMeO-phenyl 1486 —CH₂CH₂— bond bond 2,6-diMeO-phenyl 1487 —CH₂CH₂— bond bond 3,4-diMeO-phenyl 1488 —CH₂CH₂— bond bond 3,5-diMeO-phenyl 1489 —CH₂CH₂— bond bond cyclopropyl 1490 —CH₂CH₂— bond bond cyclobutyl 1491 —CH₂CH₂— bond bond cyclopentyl 1492 —CH₂CH₂— bond bond cyclohexyl 1493 —CH₂CH₂— bond bond 2-furanyl 1494 —CH₂CH₂— bond bond 2-thienyl 1495 —CH₂CH₂— bond bond 2-imidazolyl 1496 —CH₂CH₂— bond bond 2-pyridyl 1497 —CH₂CH₂— bond bond 3-pyridyl 1498 —CH₂CH₂— bond bond 4-pyridyl 1499 —CH₂CH₂— bond bond N-morpholinyl 1500 —CH₂CH₂— bond bond N-piperidinyl 1501 —CH₂CH₂— bond bond 3-Me-2-pyridyl 1502 —CH₂CH₂— bond bond 4-Me-2-pyridyl 1503 —CH₂CH₂— bond bond 1-indolyl 1504 —CH₂CH₂— bond bond 2-benzothienyl 1505 —CH₂CH₂— bond bond 2-benzofuranyl 1506 —CH₂CH₂— bond bond 1-benzimidazole 1507 —CH₂CH₂— bond bond 2-naphthyl 1508 —CH₂CH₂CH₂— bond bond phenyl 1509 —CH₂CH₂CH₂— bond bond 3,3-diphenyl 1510 —CH₂CH₂CH₂— bond bond 2-F-phenyl 1511 —CH₂CH₂CH₂— bond bond 3-F-phenyl 1512 —CH₂CH₂CH₂— bond bond 4-F-phenyl 1513 —CH₂CH₂CH₂— bond bond 2-Cl-phenyl 1514 —CH₂CH₂CH₂— bond bond 3-Cl-phenyl 1515 —CH₂CH₂CH₂— bond bond 4-Cl-phenyl 1516 —CH₂CH₂CH₂— bond bond 2-Me-phenyl 1517 —CH₂CH₂CH₂— bond bond 3-Me-phenyl 1518 —CH₂CH₂CH₂— bond bond 4-Me-phenyl 1519 —CH₂CH₂CH₂— bond bond 2-MeO-phenyl 1520 —CH₂CH₂CH₂— bond bond 3-MeO-phenyl 1521 —CH₂CH₂CH₂— bond bond 4-MeO-phenyl 1522 —CH₂CH₂CH₂— bond bond 2-MeS-phenyl 1523 —CH₂CH₂CH₂— bond bond 3-MeS-phenyl 1524 —CH₂CH₂CH₂— bond bond 4-MeS-phenyl 1525 —CH₂CH₂CH₂— bond bond 2-F₃C-phenyl 1526 —CH₂CH₂CH₂— bond bond 3-F₃C-phenyl 1527 —CH₂CH₂CH₂— bond bond 4-F₃C-phenyl 1528 —CH₂CH₂CH₂— bond bond 2,3-diF-phenyl 1529 —CH₂CH₂CH₂— bond bond 2,4-diF-phenyl 1530 —CH₂CH₂CH₂— bond bond 2,5-diF-phenyl 1531 —CH₂CH₂CH₂— bond bond 2,6-diF-phenyl 1532 —CH₂CH₂CH₂— bond bond 3,4-diF-phenyl 1533 —CH₂CH₂CH₂— bond bond 3,5-diF-phenyl 1534 —CH₂CH₂CH₂— bond bond 2,3-diCl-phenyl 1535 —CH₂CH₂CH₂— bond bond 2,4-diCl-phenyl 1536 —CH₂CH₂CH₂— bond bond 2,5-diCl-phenyl 1537 —CH₂CH₂CH₂— bond bond 2,6-diCl-phenyl 1538 —CH₂CH₂CH₂— bond bond 3,4-diCl-phenyl 1539 —CH₂CH₂CH₂— bond bond 3,5-diCl-phenyl 1540 —CH₂CH₂CH₂— bond bond 2-Cl-3-F-phenyl 1541 —CH₂CH₂CH₂— bond bond 2-Cl-4-F-phenyl 1542 —CH₂CH₂CH₂— bond bond 2-Cl-5-F-phenyl 1543 —CH₂CH₂CH₂— bond bond 3-Cl-4-F-phenyl 1544 —CH₂CH₂CH₂— bond bond 3-Cl-5-F-phenyl 1545 —CH₂CH₂CH₂— bond bond 4-Cl-2-F-phenyl 1546 —CH₂CH₂CH₂— bond bond 4-Cl-3-F-phenyl 1547 —CH₂CH₂CH₂— bond bond 2,3-diMeO-phenyl 1548 —CH₂CH₂CH₂— bond bond 2,4-diMeO-phenyl 1549 —CH₂CH₂CH₂— bond bond 2,5-diMeO-phenyl 1550 —CH₂CH₂CH₂— bond bond 2,6-diMeO-phenyl 1551 —CH₂CH₂CH₂— bond bond 3,4-diMeO-phenyl 1552 —CH₂CH₂CH₂— bond bond 3,5-diMeO-phenyl 1553 —CH₂CH₂CH₂— bond bond cyclopropyl 1554 —CH₂CH₂CH₂— bond bond cyclobutyl 1555 —CH₂CH₂CH₂— bond bond cyclopentyl 1556 —CH₂CH₂CH₂— bond bond cyclohexyl 1557 —CH₂CH₂CH₂— bond bond 2-furanyl 1558 —CH₂CH₂CH₂— bond bond 2-thienyl 1559 —CH₂CH₂CH₂— bond bond 2-imidazolyl 1560 —CH₂CH₂CH₂— bond bond 2-pyridyl 1561 —CH₂CH₂CH₂— bond bond 3-pyridyl 1562 —CH₂CH₂CH₂— bond bond 4-pyridyl 1563 —CH₂CH₂CH₂— bond bond N-morpholinyl 1564 —CH₂CH₂CH₂— bond bond N-piperidinyl 1565 —CH₂CH₂CH₂— bond bond 3-Me-2-pyridyl 1566 —CH₂CH₂CH₂— bond bond 4-Me-2-pyridyl 1567 —CH₂CH₂CH₂— bond bond 1-indolyl 1568 —CH₂CH₂CH₂— bond bond 2-benzotl-iienyl 1569 —CH₂CH₂CH₂— bond bond 2-benzofuranyl 1570 —CH₂CH₂CH₂— bond bond 1-benzimidazole 1571 —CH₂CH₂CH₂— bond bond 2-naphthyl 1572 —CH₂CH₂— bond —O— phenyl 1573 —CH₂CH₂— bond —O— 3,3- diphenylmethyl 1574 —CH₂CH₂— bond —O— 2-F-phenyl 1575 —CH₂CH₂— bond —O— 3-F-phenyl 1576 —CH₂CH₂— bond —O— 4-F-phenyl 1577 —CH₂CH₂— bond —O— 2-Cl-phenyl 1578 —CH₂CH₂— bond —O— 3-Cl-phenyl 1579 —CH₂CH₂— bond —O— 4-Cl-phenyl 1580 —CH₂CH₂— bond —O— 2-Me-phenyl 1581 —CH₂CH₂— bond —O— 3-Me-phenyl 1582 —CH₂CH₂— bond —O— 4-Me-phenyl 1583 —CH₂CH₂— bond —O— 2-MeO-phenyl 1584 —CH₂CH₂— bond —O— 3-MeO-phenyl 1585 —CH₂CH₂— bond —O— 4-MeO-phenyl 1586 —CH₂CH₂— bond —O— 2-MeS-phenyl 1587 —CH₂CH₂— bond —O— 3-HeS-phenyl 1588 —CH₂CH₂— bond —O— 4-MeS-phenyl 1589 —CH₂CH₂— bond —O— 2-F₃C-phenyl 1590 —CH₂CH₂— bond —O— 3-F₃C-phenyl 1591 —CH₂CH₂— bond —O— 4-F₃C-phenyl 1592 —CH₂CH₂— bond —O— 2,3-diF-phenyl 1593 —CH₂CH₂— bond —O— 2,4-diF-phenyl 1594 —CH₂CH₂— bond —O— 2,5-diF-phenyl 1595 —CH₂CH₂— bond —O— 2,6-diF-phenyl 1596 —CH₂CH₂— bond —O— 3,4-diF-phenyl 1597 —CH₂CH₂— bond —O— 3,5-diF-phenyl 1598 —CH₂CH₂— bond —O— 2,3-diCl-phenyl 1599 —CH₂CH₂— bond —O— 2,4-diCl-phenyl 1600 —CH₂CH₂— bond —O— 2,5-diCl-phenyl 1601 —CH₂CH₂— bond —O— 2,6-diCl-phenyl 1602 —CH₂CH₂— bond —O— 3~4-diCl-phenyl 1603 —CH₂CH₂— bond —O— 3,5-diCl-phenyl 1604 —CH₂CH₂— bond —O— 2-Cl-3-F-phenyl 1605 —CH₂CH₂— bond —O— 2-Cl-4-F-phenyl 1606 —CH₂CH₂— bond —O— 2-Cl-5-F-phenyl 1607 —CH₂CH₂— bond —O— 3-Cl-4-F-phenyl 1608 —CH₂CH₂— bond —O— 3-Cl-5-F-phenyl 1609 —CH₂CH₂— bond —O— 4-Cl-2-F-phenyl 1610 —CH₂CH₂— bond —O— 4-Cl-3-F-phenyl 1611 —CH₂CH₂— bond —O— 2,3-diMeo-phenyl 1612 —CH₂CH₂— bond —O— 2,4-diMeO-phenyl 1613 —CH₂CH₂— bond —O— 2,5-diMeo-phenyl 1614 —CH₂CH₂— bond —O— 2 6-diMeo-phenyl 1615 —CH₂CH₂— bond —O— 3,4-diMeo-phenyl 1616 —CH₂CH₂— bond —O— 3,5-diMeO-phenyl 1617 —CH₂CH₂— bond —O— cyclopropyl 1618 —CH₂CH₂— bond —O— cyclobutyl 1619 —CH₂CH₂— bond —O— cyclopentyl 1620 —CH₂CH₂— bond —O— cyclohexyl 1621 —CH₂CH₂— bond —O— 2-furanyl 1622 —CH₂CH₂— bond —O— 2-thienyl 1623 —CH₂CH₂— bond —O— 2-pyridyl 1624 —CH₂CH₂— bond —O— 3-pyridyl 1625 —CH₂CH₂— bond —O— 4-pyridyl 1626 —CH₂CH₂— bond —O— 3-Me-2-pyridyl 1627 —CH₂CH₂— bond —O— 4-Me-2-pyridyl 1628 —CH₂CH₂— bond —O— 2-benzothienyl 1629 —CH₂CH₂— bond —O— 2-benzofuranyl 1630 —CH₂CH₂— bond —O— 2-naphthyl 1631 —CH₂CH₂CH₂— bond —O— phenyl 1632 —CH₂CH₂CH₂— bond —O— 3,3- diphenylmethyl 1633 —CH₂CH₂CH₂— bond —O— 2-F-phenyl 1634 —CH₂CH₂CH₂— bond —O— 3-F-phenyl 1635 —CH₂CH₂CH₂— bond —O— 4-F-phenyl 1636 —CH₂CH₂CH₂— bond —O— 2-Cl-phenyl 1637 —CH₂CH₂CH₂— bond —O— 3-Cl-phenyl 1638 —CH₂CH₂CH₂— bond —O— 4-Cl-phenyl 1639 —CH₂CH₂CH₂— bond —O— 2-Me-phenyl 1640 —CH₂CH₂CH₂— bond —O— 3-Me-phenyl 1641 —CH₂CH₂CH₂— bond —O— 4-Me-phenyl 1642 —CH₂CH₂CH₂— bond —O— 2-MeO-phenyl 1643 —CH₂CH₂CH₂— bond —O— 3-MeO-phenyl 1644 —CH₂CH₂CH₂— bond —O— 4-MeO-phenyl 1645 —CH₂CH₂CH₂— bond —O— 2-MeS-phenyl 1646 —CH₂CH₂CH₂— bond —O— 3-MeS-phenyl 1647 —CH₂CH₂CH₂— bond —O— 4-MeS-phenyl 1648 —CH₂CH₂CH₂— bond —O— 2-F₃C-phenyl 1649 —CH₂CH₂CH₂— bond —O— 3-F₃C-phenyl 1650 —CH₂CH₂CH₂— bond —O— 4-F₃C-phenyl 1651 —CH₂CH₂CH₂— bond —O— 2,3-diF-phenyl 1652 —CH₂CH₂CH₂— bond —O— 2,4-diF-phenyl 1653 —CH₂CH₂CH₂— bond —O— 2,5-diF-phenyl 1654 —CH₂CH₂CH₂— bond —O— 2,6-diF-phenyl 1655 —CH₂CH₂CH₂— bond —O— 3,4-diF-phenyl 1656 —CH₂CH₂CH₂— bond —O— 3,5-diF-phenyl 1657 —CH₂CH₂CH₂— bond —O— 2,3-diCl-phenyl 1658 —CH₂CH₂CH₂— bond —O— 2,4-diCl-phenyl 1659 —CH₂CH₂CH₂— bond —O— 2,5-diCl-phenyl 1660 —CH₂CH₂CH₂— bond —O— 2,6-diCl-phenyl 1661 —CH₂CH₂CH₂— bond —O— 3,4-diCl-phenyl 1662 —CH₂CH₂CH₂— bond —O— 3,5-diCl-phenyl 1663 —CH₂CH₂CH₂— bond —O— 2-Cl-3-F-phenyl 1664 —CH₂CH₂CH₂— bond —O— 2-Cl-4-F-phenyl 1665 —CH₂CH₂CH₂— bond —O— 2-Cl-5-F-phenyl 1666 —CH₂CH₂CH₂— bond —O— 3-Cl-4-F-phenyl 1667 —CH₂CH₂CH₂— bond —O— 3-Cl-5-F-phenyl 1668 —CH₂CH₂CH₂— bond —O— 4-Cl-2-F-phenyl 1669 —CH₂CH₂CH₂— bond —O— 4-Cl-3-F-phenyl 1670 —CH₂CH₂CH₂— bond —O— 2,3-diMeo-phenyl 1671 —CH₂CH₂CH₂— bond —O— 2,4-diMeO-phenyl 1672 —CH₂CH₂CH₂— bond —O— 2,5-diMeo-phenyl 1673 —CH₂CH₂CH₂— bond —O— 2,6-diMeO-phenyl 1674 —CH₂CH₂CH₂— bond —O— 3,4-diMeO-phenyl 1675 —CH₂CH₂CH₂— bond —O— 3,5-diMeo-phenyl 1676 —CH₂CH₂CH₂— bond —O— cyclopropyl 1677 —CH₂CH₂CH₂— bond —O— cyclobutyl 1678 —CH₂CH₂CH₂— bond —O— cyclopentyl 1679 —CH₂CH₂CH₂— bond —O— cyclohexyl 1680 —CH₂CH₂CH₂— bond —O— 2-furanyl 1681 —CH₂CH₂CH₂— bond —O— 2-thienyl 1682 —CH₂CH₂CH₂— bond —O— 2-pyridyl 1683 —CH₂CH₂CH₂— bond —O— 3-pyridyl 1684 —CH₂CH₂CH₂— bond —O— 4-pyridyl 1685 —CH₂CH₂CH₂— bond —O— 3-Me-2-pyridyl 1686 —CH₂CH₂CH₂— bond —O— 4-Me-2-pyridyl 1687 —CH₂CH₂CH₂— bond —O— 2-benzothienyl 1688 —CH₂CH₂CH₂— bond —O— 2-benzofuranyl 1689 —CH₂CH₂CH₂— bond —O— 2-naphthyl wherein R³ and R⁵ are:

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1.-21. (canceled)
 22. A compound or a pharmaceutically acceptable salt form thereof, selected from: (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-ethoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopropylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclobutylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methoxyphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-trifluoromethylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(4-methylphenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2,4-dichlorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(3-chloro-4-fluorophenyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzophenon-3-yl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; and (2R,3S)N1-[1,3,4,5-tetrahydro-1-(3-(2-naphthyl)benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(cyclopentylmethyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(propyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(benzyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(phenethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-((4-fluorophenyl)methyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylmethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopropylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclobutylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclopentylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide; and (2R,3S)N1-[1,3,4,5-tetrahydro-1-(cyclohexylethyl)-2-oxo-5-(phenyl)-2H-1,5-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(butyl)-butanediamide.
 23. (canceled)
 24. A pharmaceutical composition comprising a compound of claim 22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 25. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 22 or a pharmaceutically acceptable salt thereof.
 26. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound, (2S,3R)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide,

or a pharmaceutically acceptable salt thereof. 27.-30. (canceled)
 31. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a metalloprotease inhibitor selected from a compound as claimed in claim 22, or a pharmaceutically acceptable salt thereof, which inhibits γ-secretase activity.
 32. (canceled)
 33. The method of claim 31 wherein the metalloprotease inhibitor has an IC₅₀ value of less than 10 μM in the Aβ immunoprecipitation assay.
 34. (canceled)
 35. A method for the treatment of Alzheimer's Disease associated with β-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a metalloprotease inhibitor compound as claimed in claim 26, or a pharmaceutically acceptable salt thereof, which inhibits γ-secretase activity.
 36. The method of claim 35 wherein the metalloprotease inhibitor has an IC₅₀ value of less than 10 μM in the Aβ immunoprecipitation assay.
 37. A pharmaceutical composition comprising a compound, (2S,3R)N1-[1,3-dihydro-1-(3-phenoxybenzyl)-2-oxo-5-(phenyl)-2H-1,4-benzodiazepin-3-yl]-2-(2-methylpropyl)-3-(allyl)-butanediamide,

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 